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1
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Fu T, Mohan M, Bose M, Brennan EP, Kiriazis H, Deo M, Nowell CJ, Godson C, Cooper ME, Zhao P, Kemp-Harper BK, Woodman OL, Ritchie RH, Kantharidis P, Qin CX. Lipoxin A 4 improves cardiac remodeling and function in diabetes-associated cardiac dysfunction. Cardiovasc Diabetol 2024; 23:413. [PMID: 39563316 PMCID: PMC11577589 DOI: 10.1186/s12933-024-02501-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/04/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A4 (LXA4), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought. Thus, we aimed to determine whether LXA4 therapeutic treatment attenuates diabetes-induced cardiac pathology. METHODS Six-week-old male apolipoprotein E-deficient (ApoE-/-) mice were followed for 16 weeks after injection of streptozotocin (STZ, 55 mg/kg/day, i.p. for 5 days) to induce type-1 diabetes (T1DM). Treatment with LXA4 (5 μg/kg, i.p.) or vehicle (0.02% ethanol, i.p.) was administered twice weekly for the final 6 weeks. One week before endpoint, echocardiography was performed within a subset of mice from each group. At the end of the study, mice were euthanized with sodium pentobarbital (100 mg/kg i.p.) and hearts were collected for ex vivo analysis, including histological assessment, gene expression profiling by real-time PCR and protein level measurement by western blot. RESULTS As expected diabetic mice showed a significant elevation in plasma glycated hemoglobin (HbA1c) and glucose levels, along with reduced body weight. Vehicle-treated diabetic mice exhibited increased cardiac inflammation, macrophage content, and an elevated ratio of M1-like to M2-like macrophage markers. In addition, myocardial fibrosis, cardiomyocytes apoptosis and hypertrophy (at the genetic level) were evident, with echocardiography revealing early signs of left ventricular (LV) diastolic dysfunction. Treatment with LXA4 ameliorated diabetes-induced cardiac inflammation, pro-inflammatory macrophage polarization and cardiac remodeling (especially myocardial fibrosis and cardiomyocytes apoptosis), with ultimate improvement in cardiac function. Of note, this improvement was independent of glucose control. CONCLUSIONS These findings demonstrated that LXA4 treatment attenuated the extent of cardiac inflammation in diabetic hearts, resulting in limited cardiac remodeling and improved LV diastolic function. This supports further exploration of LXA4-based therapy for the management of diabetic heart disease. The recent development of stable LXA4 mimetics holds potential as a novel strategy to treat cardiac dysfunction in diabetes, paving the way for innovative and more effective therapeutic strategies.
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MESH Headings
- Animals
- Lipoxins/pharmacology
- Male
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/complications
- Ventricular Remodeling/drug effects
- Diabetic Cardiomyopathies/physiopathology
- Diabetic Cardiomyopathies/etiology
- Diabetic Cardiomyopathies/metabolism
- Diabetic Cardiomyopathies/drug therapy
- Ventricular Function, Left/drug effects
- Mice, Knockout, ApoE
- Anti-Inflammatory Agents/pharmacology
- Fibrosis
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 1/metabolism
- Macrophages/drug effects
- Macrophages/metabolism
- Ventricular Dysfunction, Left/physiopathology
- Ventricular Dysfunction, Left/etiology
- Ventricular Dysfunction, Left/metabolism
- Ventricular Dysfunction, Left/drug therapy
- Ventricular Dysfunction, Left/prevention & control
- Mice, Inbred C57BL
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Myocardium/pathology
- Myocardium/metabolism
- Mice
- Apoptosis/drug effects
- Inflammation Mediators/metabolism
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Affiliation(s)
- Ting Fu
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Muthukumar Mohan
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Madhura Bose
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Eoin P Brennan
- Diabetes Complications Research Centre, School of Medicine and Conway Institute, University College Dublin, Dublin, Ireland
| | - Helen Kiriazis
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Minh Deo
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Cameron J Nowell
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Catherine Godson
- Diabetes Complications Research Centre, School of Medicine and Conway Institute, University College Dublin, Dublin, Ireland
| | - Mark E Cooper
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Peishen Zhao
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Barbara K Kemp-Harper
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Owen L Woodman
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Rebecca H Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Phillip Kantharidis
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Cheng Xue Qin
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
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2
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Hao Y, Wang W, Zhang L, Li W. Pyroptosis in asthma: inflammatory phenotypes, immune and non-immune cells, and novel treatment approaches. Front Pharmacol 2024; 15:1452845. [PMID: 39611173 PMCID: PMC11603363 DOI: 10.3389/fphar.2024.1452845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/06/2024] [Indexed: 11/30/2024] Open
Abstract
Pyroptosis is a form of inflammatory programmed cell death, and is activated by pathogen infections or endogenous danger signals. The canonical pyroptosis process is characterized by the inflammasome (typically NLRP3)-mediated activation of caspase-1, which in turn cleaves and activates IL-1β and IL-18, as well as gasdermin D, which is a pore-forming executor protein, leading to cell membrane rupture, and the release of proinflammatory cytokines and damage-associated molecular pattern molecules. Pyroptosis is considered a part of the innate immune response. A certain level of pyroptosis can help eliminate pathogenic microorganisms, but excessive pyroptosis can lead to persistent inflammatory responses, and cause tissue damage. In recent years, pyroptosis has emerged as a crucial contributor to the development of chronic inflammatory respiratory diseases, such as asthma. The present study reviews the involvement of pyroptosis in the development of asthma, in terms of its role in different inflammatory phenotypes of the disease, and its influence on various immune and non-immune cells in the airway. In addition, the potential therapeutic value of targeting pyroptosis for the treatment of specific phenotypes of asthma is discussed.
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Affiliation(s)
- Yuqiu Hao
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wenrui Wang
- Department of Hepatopancreatobiliary Medicine, Digestive Diseases Center, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Lin Zhang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Li
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
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3
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Zheng W, Marini W, Murakami K, Sotov V, Butler M, Gorrini C, Ohashi PS, Reedijk M. Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy. Nat Commun 2024; 15:8514. [PMID: 39353903 PMCID: PMC11445480 DOI: 10.1038/s41467-024-52553-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 09/12/2024] [Indexed: 10/03/2024] Open
Abstract
Tumor immune microenvironment (TIME) spatial organization predicts outcome and therapy response in triple-negative breast cancer (TNBC). An immunosuppressive TIME containing elevated tumor-associated macrophages (TAM) and scarce CD8+ T cells is associated with poor outcome, but the regulatory mechanisms are poorly understood. Here we show that ETS1-driven caspase-1 expression, required for IL1β processing and TAM recruitment, is negatively regulated by estrogen receptors alpha (ERα) and a defining feature of TNBC. Elevated tumoral caspase-1 is associated with a distinct TIME characterized by increased pro-tumoral TAMs and CD8+ T cell exclusion from tumor nests. Mouse models prove the functional importance of ERα, ETS1, caspase-1 and IL1β in TIME conformation. Caspase-1 inhibition induces an immunoreactive TIME and reverses resistance to immune checkpoint blockade, identifying a therapeutically targetable mechanism that governs TNBC spatial organization.
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Affiliation(s)
- Weiyue Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Wanda Marini
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Kiichi Murakami
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Valentin Sotov
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Marcus Butler
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON, Canada
| | - Chiara Gorrini
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- School of Molecular and Cellular Biology, University of Leeds, Leeds, UK
| | - Pamela S Ohashi
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Michael Reedijk
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
- Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
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Zhen H, Hu Y, Liu X, Fan G, Zhao S. The protease caspase-1: Activation pathways and functions. Biochem Biophys Res Commun 2024; 717:149978. [PMID: 38718564 DOI: 10.1016/j.bbrc.2024.149978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/18/2024] [Accepted: 04/22/2024] [Indexed: 05/21/2024]
Abstract
Caspase-1 is one of the main mediators of inflammatory caspases and has become a correspondent with inflammation, cell death, and several inflammatory diseases. In this review, we systematically summarize both original and recent advances in caspase-1 to provide references for a better understanding of the molecular mechanisms in its activation and functions. This study investigates and summarizes the published articles concerning caspase-1, inflammation, pyroptosis, apoptosis, and cell death by searching academic search systems, including the PubMed, Web of Science, and Google Scholar. Caspase-1 is one of the main mediators of inflammatory caspases and has become a correspondent with inflammation and cell death. In cell death, caspase-1 was originally found to cause apoptosis in fibroblasts. Importantly, caspase-1 was later reported to execute programmed cell death, including pyroptosis and apoptosis, in many immune cells in response to diverse stimuli. It is widely established that different pathways can activate caspase-1 and subsequently mediate cell death and inflammation. It has become increasingly clear that caspase-1 is responsible for the initiation and control of pyroptosis, apoptosis, and inflammation in addition to its well-known function in cleaving IL-1β. The significant advancement in the understanding of caspase-1-controlled cell death and novel substrates inspires new therapeutic approaches in the future.
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Affiliation(s)
- Hongmin Zhen
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology & Business University (BTBU), Beijing, 100048, China
| | - Yumeng Hu
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology & Business University (BTBU), Beijing, 100048, China
| | - Xiaoyan Liu
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology & Business University (BTBU), Beijing, 100048, China
| | - Guangsen Fan
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology & Business University (BTBU), Beijing, 100048, China
| | - Shuna Zhao
- Beijing Engineering and Technology Research Center of Food Additives, Beijing Technology & Business University (BTBU), Beijing, 100048, China.
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5
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Cheng C, Hsu SK, Chen YC, Liu W, Shu ED, Chien CM, Chiu CC, Chang WT. Burning down the house: Pyroptosis in the tumor microenvironment of hepatocellular carcinoma. Life Sci 2024; 347:122627. [PMID: 38614301 DOI: 10.1016/j.lfs.2024.122627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 03/20/2024] [Accepted: 04/10/2024] [Indexed: 04/15/2024]
Abstract
A high mortality rate makes hepatocellular carcinoma (HCC) a difficult cancer to treat. When surgery is not possible, liver cancer patients are treated with chemotherapy. However, HCC management and treatment are difficult. Sorafenib, which is a first-line treatment for hepatocellular carcinoma, initially slows disease progression. However, sorafenib resistance limits patient survival. Recent studies have linked HCC to programmed cell death, which has increased researcher interest in therapies targeting cell death. Pyroptosis, which is an inflammatory mode of programmed cell death, may be targeted to treat HCC. Pyroptosis pathways, executors, and effects are examined in this paper. This review summarizes how pyroptosis affects the tumor microenvironment (TME) in HCC, including the role of cytokines such as IL-1β and IL-18 in regulating immune responses. The use of chemotherapies and their ability to induce cancer cell pyroptosis as alternative treatments and combining them with other drugs to reduce side effects is also discussed. In conclusion, we highlight the potential of inducing pyroptosis to treat HCC and suggest ways to improve patient outcomes. Studies on cancer cell pyroptosis may lead to new HCC treatments.
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Affiliation(s)
- Chi Cheng
- School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Sheng-Kai Hsu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yen-Chun Chen
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Wangta Liu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - En-De Shu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ching-Ming Chien
- Department of Medical Sciences Industry, College of Health Sciences, Chang Jung Christian University, Tainan 711, Taiwan
| | - Chien-Chih Chiu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; The Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Wen-Tsan Chang
- Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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6
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Devarajan J, Mena S, Cheng J. Mechanisms of complex regional pain syndrome. FRONTIERS IN PAIN RESEARCH 2024; 5:1385889. [PMID: 38828388 PMCID: PMC11140106 DOI: 10.3389/fpain.2024.1385889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/16/2024] [Indexed: 06/05/2024] Open
Abstract
Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder characterized by a diverse array of symptoms, including pain that is disproportionate to the initial triggering event, accompanied by autonomic, sensory, motor, and sudomotor disturbances. The primary pathology of both types of CRPS (Type I, also known as reflex sympathetic dystrophy, RSD; Type II, also known as causalgia) is featured by allodynia, edema, changes in skin color and temperature, and dystrophy, predominantly affecting extremities. Recent studies started to unravel the complex pathogenic mechanisms of CRPS, particularly from an autoimmune and neuroimmune interaction perspective. CRPS is now recognized as a systemic disease that stems from a complex interplay of inflammatory, immunologic, neurogenic, genetic, and psychologic factors. The relative contributions of these factors may vary among patients and even within a single patient over time. Key mechanisms underlying clinical manifestations include peripheral and central sensitization, sympathetic dysregulation, and alterations in somatosensory processing. Enhanced understanding of the mechanisms of CRPS is crucial for the development of effective therapeutic interventions. While our mechanistic understanding of CRPS remains incomplete, this article updates recent research advancements and sheds light on the etiology, pathogenesis, and molecular underpinnings of CRPS.
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Affiliation(s)
- Jagan Devarajan
- Department of Pain Management, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Shayla Mena
- Department of Pain Management, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Jianguo Cheng
- Department of Pain Management and Neurosciences, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
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7
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Azhar G, Nagano K, Patyal P, Zhang X, Verma A, Wei JY. Deletion of Interleukin-1β Converting Enzyme Alters Mouse Cardiac Structure and Function. BIOLOGY 2024; 13:172. [PMID: 38534442 DOI: 10.3390/biology13030172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 02/07/2024] [Accepted: 03/04/2024] [Indexed: 03/28/2024]
Abstract
Interleukin-1β converting enzyme (ICE, caspase-1) is a thiol protease that cleaves the pro-inflammatory cytokine precursors of IL-1β and IL-18 into active forms. Given the association between caspase-1 and cardiovascular pathology, we analyzed the hearts of ICE knockout (ICE KO) mice to test the hypothesis that caspase-1 plays a significant role in cardiac morphology and function. We characterized the histological and functional changes in the hearts of ICE KO mice compared to the Wild type. The cardiomyocytes from the neonatal ICE KO mice showed an impaired response to oxidative stress. Subsequently, the hearts from the ICE KO mice were hypertrophied, with a significant increase in the left ventricular and septal wall thickness and a greater LV mass/body weight ratio. The ICE KO mice hearts exhibited irregular myofibril arrangements and disruption of the cristae in the mitochondrial structure. Proapoptotic proteins that were significantly increased in the hearts of ICE KO versus the Wild type included pErk, pJNK, p53, Fas, Bax, and caspase 3. Further, the antiapoptotic proteins Bag-1 and Bcl-2 are activated in ICE KO hearts. Functionally, there was an increase in the left ventricular epicardial diameter and volume in ICE KO. In conclusion, our findings support the important role of caspase-1 in maintaining cardiac health; specifically, a significant decrease in caspase-1 is detrimental to the cardiovascular system.
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Affiliation(s)
- Gohar Azhar
- Donald W. Reynolds Department of Geriatrics, Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Koichiro Nagano
- Donald W. Reynolds Department of Geriatrics, Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Pankaj Patyal
- Donald W. Reynolds Department of Geriatrics, Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Xiaomin Zhang
- Donald W. Reynolds Department of Geriatrics, Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Ambika Verma
- Donald W. Reynolds Department of Geriatrics, Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Jeanne Y Wei
- Donald W. Reynolds Department of Geriatrics, Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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Zhang M, Yu A, Wu H, Xiong X, Li J, Chen L. Lactobacillus acidophilus and Bacillus subtilis significantly change the growth performance, serum immunity and cecal microbiota of Cherry Valley ducks during the fattening period. Anim Sci J 2024; 95:e13946. [PMID: 38651265 DOI: 10.1111/asj.13946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 02/16/2024] [Accepted: 03/10/2024] [Indexed: 04/25/2024]
Abstract
This study explored the effects of a Bacillus subtilis and Lactobacillus acidophilus mixture containing the co-fermented products of the two probiotics on growth performance, serum immunity and cecal microbiota of Cherry Valley ducks. This study included 480 one-day-old Cherry Valley ducks divided into four feeding groups: basal diet (control group) and basal diet supplemented with 300, 500, or 700 mg/kg of the probiotic powder; the ducks were raised for 42 days. Compared with the control group, body weight on day 42 and the average daily gain on days 15-42 significantly increased (p < 0.05), and the feed conversion rate significantly decreased (p < 0.05) in the experimental groups. Furthermore, the serum immunoglobulin (Ig) A, IgG, IgM, and interleukin (IL)-4 levels increased significantly (p < 0.05), and IL-1β, IL-2, and tumor necrosis factor-α decreased significantly (p < 0.05) in the experimental groups. Finally, Sellimonas, Prevotellaceae NK3B31 group, Lachnospiraceae NK4A136 group and Butyricoccus played an important role in the cecal microbiota of the experimental group. Thus, the probiotic powder has impacts on the growth performance, serum immunity and cecal microbiota of Cherry Valley Ducks.
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Affiliation(s)
- Menghui Zhang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Animal Science & Veterinary, Zhejiang Academy of Agricultural Science, Hangzhou, China
- College of Animal Science, Shanxi Agricultural University, Jinzhong, China
| | - Anan Yu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Animal Science & Veterinary, Zhejiang Academy of Agricultural Science, Hangzhou, China
| | - Hongzhi Wu
- Chinese Academy of Tropical Agricultural Sciences Tropical Crops Genetic Resources Insititute, Haikou, China
| | - Xiaolan Xiong
- Institute of Animal Husbandry and Veterinary Medicine, Jiangxi Academy of Agricultural Sciences, Nanchang, China
| | - Jianhui Li
- College of Animal Science, Shanxi Agricultural University, Jinzhong, China
| | - Li Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Animal Science & Veterinary, Zhejiang Academy of Agricultural Science, Hangzhou, China
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Galindo-Moreno P, Montalvo-Acosta S, Martín-Morales N, Carrillo-Gálvez AB, González-Rey E, O'Valle F, Padial-Molina M. Inflammasomes NLRP3 and AIM2 in peri-implantitis: A cross-sectional study. Clin Oral Implants Res 2023; 34:1342-1353. [PMID: 37642257 DOI: 10.1111/clr.14174] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 07/18/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Inflammasome components NLRP3 and AIM2 contribute to inflammation development by the activation of caspase-1 and IL-1β. They have not been yet evaluated in samples from patients with active peri-implantitis. Thus, the aim of the present study is to analyze the expression of inflammasomes NLRP3 and AIM2 and subsequent caspase 1 and IL-1β assessing the microenvironment of leukocyte subsets in samples from patients with active peri-implantitis. METHODS Biopsies were collected from 33 implants in 21 patients being treated for peri-implantitis. Biopsies from gingival tissues from 15 patients with healthy periodontium were also collected for control. These tissues were evaluated through conventional histological stainings. Then, immunohistochemical detection was performed to analyze NLRP3, AIM2, caspase-1, and IL-1β and markers of different leukocyte subsets. PCR for inflammasomes and related genes was also done. RESULTS This manuscript reveals a high immunohistochemical and mRNA expression of NLRP3 and AIM2 inflammasomes, caspase-1, and IL-1β in biopsies collected from human peri-implantitis. The expression of the tested markers was significantly correlated with the increase in inflammatory infiltrate, probing depth, presence of biofilm, and bleeding on probing. In these peri-implantitis lesions, the area of biopsy tissue occupied by inflammatory infiltrate was intense while the area occupied by collagen was significantly lower. In comparison with periodontal healthy tissues, the inflammatory infiltrate was statistically significantly higher in the peri-implantitis biopsies and was mainly composed of plasma cells, followed by T and B lymphocytes. CONCLUSION In human peri-implantitis, chronic inflammation can be explained in part by the action of IL-1β/caspase 1 induced through NLRP3 and AIM2 inflammasome activation.
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Affiliation(s)
- Pablo Galindo-Moreno
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain
| | - Saray Montalvo-Acosta
- PhD Program in Clinical Medicine and Public Health, University of Granada, Granada, Spain
| | - Natividad Martín-Morales
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain
- PhD Program in Biomedicine, University of Granada, Granada, Spain
- Department of Pathology, School of Medicine, University of Granada, Granada, Spain
| | | | - Elena González-Rey
- Institute of Parasitology and Biomedicine Lopez-Neyra, IPBLN-CSIC, Parque Tecnologico de la Salud, Granada, Spain
| | - Francisco O'Valle
- Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain
- Department of Pathology, School of Medicine, University of Granada, Granada, Spain
- Institute of Biopathology and Regenerative Medicine (IBIMER, CIBM), University of Granada, Granada, Spain
| | - Miguel Padial-Molina
- Department of Oral Surgery and Implant Dentistry, School of Dentistry, University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain
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10
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Miljkovic M, Lozano S, Castellote I, de Cózar C, Villegas-Moreno AI, Gamallo P, Jimenez-Alfaro Martinez D, Fernández-Álvaro E, Ballell L, Garcia GA. Novel inhibitors that target bacterial virulence identified via HTS against intra-macrophage survival of Shigella flexneri. mSphere 2023; 8:e0015423. [PMID: 37565760 PMCID: PMC10597453 DOI: 10.1128/msphere.00154-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/02/2023] [Indexed: 08/12/2023] Open
Abstract
Shigella flexneri is a facultative intracellular pathogen that causes shigellosis, a human diarrheal disease characterized by the destruction of the colonic epithelium. Novel antimicrobial compounds to treat infections are urgently needed due to the proliferation of bacterial antibiotic resistance and lack of new effective antimicrobials in the market. Our approach to find compounds that block the Shigella virulence pathway has three potential advantages: (i) resistance development should be minimized due to the lack of growth selection pressure, (ii) no resistance due to environmental antibiotic exposure should be developed since the virulence pathways are not activated outside of host infection, and (iii) the normal intestinal microbiota, which do not have the targeted virulence pathways, should be unharmed. We chose to utilize two phenotypic assays, inhibition of Shigella survival in macrophages and Shigella growth inhibition (minimum inhibitory concentration), to interrogate the 1.7 M compound screening collection subset of the GlaxoSmithKline drug discovery chemical library. A number of secondary assays on the hit compounds resulting from the primary screens were conducted, which, in combination with chemical, structural, and physical property analyses, narrowed the final hit list to 44 promising compounds for further drug discovery efforts. The rapid development of antibiotic resistance is a critical problem that has the potential of returning the world to a "pre-antibiotic" type of environment, where millions of people will die from previously treatable infections. One relatively newer approach to minimize the selection pressures for the development of resistance is to target virulence pathways. This is anticipated to eliminate any resistance selection pressure in environmental exposure to virulence-targeted antibiotics and will have the added benefit of not affecting the non-virulent microbiome. This paper describes the development and application of a simple, reproducible, and sensitive assay to interrogate an extensive chemical library in high-throughput screening format for activity against the survival of Shigella flexneri 2457T-nl in THP-1 macrophages. The ability to screen very large numbers of compounds in a reasonable time frame (~1.7 M compounds in ~8 months) distinguishes this assay as a powerful tool in further exploring new compounds with intracellular effect on S. flexneri or other pathogens with similar pathways of pathogenesis. The assay utilizes a luciferase reporter which is extremely rapid, simple, relatively inexpensive, and sensitive and possesses a broad linear range. The assay also utilized THP-1 cells that resemble primary monocytes and macrophages in morphology and differentiation properties. THP-1 cells have advantages over human primary monocytes or macrophages because they are highly plastic and their homogeneous genetic background minimizes the degree of variability in the cell phenotype (1). The intracellular and virulence-targeted selectivity of our methodology, determined via secondary screening, is an enormous advantage. Our main interest focuses on hits that are targeting virulence, and the most promising compounds with adequate physicochemical and drug metabolism and pharmacokinetic (DMPK) properties will be progressed to a suitable in vivo shigellosis model to evaluate the therapeutic potential of this approach. Additionally, compounds that act via a host-directed mechanism could be a promising source for further research given that it would allow a whole new, specific, and controlled approach to the treatment of diseases caused by some pathogenic bacteria.
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Affiliation(s)
- Marija Miljkovic
- Department of Medical Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
- GSK Global Health Unit, Madrid, Spain
| | | | | | | | | | | | | | | | | | - George A. Garcia
- Department of Medical Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
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11
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Metcalfe S, Panasiewicz M, Kay JG. Inflammatory macrophages exploited by oral streptococcus increase IL-1B release via NLRP6 inflammasome. J Leukoc Biol 2023; 114:347-357. [PMID: 37497744 PMCID: PMC10533225 DOI: 10.1093/jleuko/qiad089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/18/2023] [Accepted: 07/24/2023] [Indexed: 07/28/2023] Open
Abstract
Chronic inflammatory periodontal disease develops in part from the infiltration of a large number of classically activated inflammatory macrophages that release inflammatory cytokines important for disease progression, including inflammasome-dependent interleukin (IL)-1β. Streptococcus gordonii is a normally commensal oral microorganism; while not causative, recent evidence indicates that commensal oral microbes are required for the full development of periodontal disease. We have recently reported that inflammatory macrophages counterintuitively allow for the increased survival of phagocytosed S. gordonii over nonactivated or alternatively activated macrophages. This survival is dependent on increased reactive oxygen species production within the phagosome of the inflammatory macrophages, and resistance by the bacterium and can result in S. gordonii damaging the phagolysosomes. Here, we show that activated macrophages infected with live S. gordonii release more IL-1β than non-activated macrophages infected with either live or dead S. gordonii, and that the survival of oral Streptococci are more dependent on macrophage activation than other Gram positive microbes, both classical pathogens and commensals. We also find that S. gordonii-dependent inflammatory macrophage inflammasome activation requires the cytoplasmic NLRP6. Overall, our results suggest S. gordonii is capable of evading immune destruction, increasing inflammatory mediators, and increasing inflammatory macrophage response, and that this ability is increased under conditions of inflammation. This work reveals additional mechanisms by which normally commensal oral streptococci-macrophage interactions can change, resulting in increased release of mature IL-1β, potentially contributing to an environment that perpetuates inflammation.
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Affiliation(s)
- Sarah Metcalfe
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, 3435 Main street, Buffalo, NY 14214, United States
| | - Michelle Panasiewicz
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, 3435 Main street, Buffalo, NY 14214, United States
| | - Jason G Kay
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, 3435 Main street, Buffalo, NY 14214, United States
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12
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Broz P. Unconventional protein secretion by gasdermin pores. Semin Immunol 2023; 69:101811. [PMID: 37473560 DOI: 10.1016/j.smim.2023.101811] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/14/2023] [Accepted: 07/14/2023] [Indexed: 07/22/2023]
Abstract
Unconventional protein secretion (UPS) allows the release of specific leaderless proteins independently of the classical endoplasmic reticulum (ER)-Golgi secretory pathway. While it remains one of the least understood mechanisms in cell biology, UPS plays an essential role in immunity as it controls the release of the IL-1 family of cytokines, which coordinate host defense and inflammatory responses. The unconventional secretion of IL-1β and IL-18, the two most prominent members of the IL-1 family, is initiated by inflammasome complexes - cytosolic signaling platforms that are assembled in response to infectious or noxious stimuli. Inflammasomes activate inflammatory caspases that proteolytically mature IL-1β/- 18, but also induce pyroptosis, a lytic form of cell death. Pyroptosis is caused by gasdermin-D (GSDMD), a member of the gasdermin protein family, which is activated by caspase cleavage and forms large β-barrel plasma membrane pores. This pore-forming activity is shared with other family members that are activated during infection or upon treatment with chemotherapy drugs. While the induction of cell death was assumed to be the main function of gasdermin pores, accumulating evidence suggests that they have also non-lytic functions, such as in the release of cytokines and alarmins, or in regulating ion fluxes. This has raised the possibility that gasdermin pores are one of the main mediators of UPS. Here, I summarize and discuss new insights into gasdermin activation and pore formation, how gasdermin pores achieve selective cargo release, and how gasdermin pore formation and ninjurin-1-driven plasma membrane rupture are executed and regulated.
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Affiliation(s)
- Petr Broz
- Department of Immunobiology, University of Lausanne, Switzerland.
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13
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Althagafy HS, Sharawi ZW, Batawi AH, Almohaimeed HM, Al-Thubiani WS, Hassanein EHM, Rateb A. Buspirone attenuated methotrexate-induced hippocampal toxicity in rats by regulating Nrf2/HO-1, PPAR-γ, NF-κB/nNOS, and ROS/NLRP3/caspase-1 signaling pathways. J Biochem Mol Toxicol 2023; 37:e23414. [PMID: 37341015 DOI: 10.1002/jbt.23414] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 06/02/2023] [Accepted: 06/08/2023] [Indexed: 06/22/2023]
Abstract
Methotrexate (MTX) is a chemotherapeutic agent widely used to treat a variety of tumors. Nonetheless, MTX-induced hippocampal neurotoxicity is a well-defined dose-limiting adverse effect that limits clinical utility. Proinflammatory cytokine production and oxidative stress are possible mechanisms for MTX-induced neurotoxicity. Buspirone (BSP), a partial agonist of the 5-HT1a receptor (5-HT1aR), has emerged as an anxiolytic drug. BSP has been shown to possess antioxidant and anti-inflammatory effects. The current study investigated BSP's potential anti-inflammatory and antioxidant effects in attenuating MTX-induced hippocampal toxicity. Rats received either BSP (1.5 mg/kg) orally for 10 days and MTX (20 mg/kg) i.p. on Day 5. BSP administration markedly protected hippocampal neurons from drastic degenerated neuronal changes induced by MTX. BSP significantly attenuated oxidative injury by downregulating Kelch-like ECH-associated protein 1 expression while potently elevating hippocampal Nrf2, heme oxygenase-1, and peroxisome proliferator-activated receptor expression. BSP dampened inflammation by reducing NO2 - , tumor necrosis factor-alpha, IL-6, and interleukin 1 beta levels mediated by downregulating NF-κB and neuronal nitric oxides synthase expression. Moreover, BSP potently counteracted hippocampal pyroptosis by downregulating NLRP3, ASC, and cleaved-caspase-1 proteins. Therefore, BSP may represent a promising approach to attenuate neurotoxicity in patients receiving MTX.
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Affiliation(s)
- Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Zeina W Sharawi
- Department Biological Science, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ashwaq H Batawi
- Department Biological Science, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hailah M Almohaimeed
- Department of Basic Science, College of Medicine, Princess Nourah Bint Abdul Rahman University, Riyadh, Saudi Arabia
| | - Wafa S Al-Thubiani
- Department of Biology, Faculty of Applied Sciences, Umm Al-Qura University, Mecca, Saudi Arabia
| | - Emad H M Hassanein
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Amal Rateb
- Department of Human Anatomy and Embryology, Faculty of Medicine, Assuit University, Assiut, Egypt
- Department of Basic Sciences, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arbia
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14
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Viil J, Somelar-Duracz K, Jaako K, Anier K, Zharkovsky A. Characterization of IMG Microglial Cell Line as a Valuable In Vitro Tool for NLRP3 Inflammasome Studies. Cell Mol Neurobiol 2023; 43:2053-2069. [PMID: 36163404 PMCID: PMC11412188 DOI: 10.1007/s10571-022-01285-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 09/14/2022] [Indexed: 11/03/2022]
Abstract
Microglial cells constantly surveil the cerebral microenvironment and become activated following injury and disease to mediate inflammatory responses. The nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome, which is abundantly expressed in microglial cells, plays a key role in these responses as well as in the development of many neurological disorders. Microglial cell lines are a valuable tool to study the causes and possible treatments for neurological diseases which are linked to inflammation. Here, we investigated whether the mouse microglial cell line IMG is suitable to study NLRP3 inflammasome by incubating cells with different concentrations of NLRP3 inflammasome priming and activating agents lipopolysaccharide (LPS) and ATP, respectively, and applying short (4 h) or long (24 h) LPS incubation times. After short LPS incubation, the mRNA levels of most pro-inflammatory and NLRP3 inflammasome-associated genes were more upregulated than after long incubation. Moreover, the combination of higher LPS and ATP concentrations with short incubation time resulted in greater levels of active forms of caspase-1 and interleukin-1 beta (IL-1β) proteins than low LPS and ATP concentrations or long incubation time. We also demonstrated that treatment with NLRP3 inflammasome inhibitor glibenclamide suppressed NLRP3 inflammasome activation in IMG cells, as illustrated by the downregulation of gasdermin D N-fragment and mature caspase-1 and IL-1β protein levels. In addition, we conducted similar experiments with primary microglial cells and BV-2 cell line to determine the similarities and differences in their responses. Overall, our results indicate that IMG cell line could be a valuable tool for NLRP3 inflammasome studies. In IMG cells, 4-h incubation with lipopolysaccharide (LPS) induces a stronger upregulation of NLRP3 inflammasome-associated pro-inflammatory genes compared to 24-h incubation. NLRP3 inflammasome is robustly activated only after the addition of 3 mM of ATP following short LPS incubation time.
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Affiliation(s)
- Janeli Viil
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia.
| | - Kelli Somelar-Duracz
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| | - Külli Jaako
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| | - Kaili Anier
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| | - Alexander Zharkovsky
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
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15
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Zhuang D, Misra SL, Mugisho OO, Rupenthal ID, Craig JP. NLRP3 Inflammasome as a Potential Therapeutic Target in Dry Eye Disease. Int J Mol Sci 2023; 24:10866. [PMID: 37446038 DOI: 10.3390/ijms241310866] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/19/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Dry eye disease (DED) is a multifactorial ocular surface disorder arising from numerous interrelated underlying pathologies that trigger a self-perpetuating cycle of instability, hyperosmolarity, and ocular surface damage. Associated ocular discomfort and visual disturbance contribute negatively to quality of life. Ocular surface inflammation has been increasingly recognised as playing a key role in the pathophysiology of chronic DED. Current readily available anti-inflammatory agents successfully relieve symptoms, but often without addressing the underlying pathophysiological mechanism. The NOD-like receptor protein-3 (NLRP3) inflammasome pathway has recently been implicated as a key driver of ocular surface inflammation, as reported in pre-clinical and clinical studies of DED. This review discusses the intimate relationship between DED and inflammation, highlights the involvement of the inflammasome in the development of DED, describes existing anti-inflammatory therapies and their limitations, and evaluates the potential of the inflammasome in the context of the existing anti-inflammatory therapeutic landscape as a therapeutic target for effective treatment of the disease.
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Affiliation(s)
- Dian Zhuang
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
| | - Stuti L Misra
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
| | - Odunayo O Mugisho
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
| | - Ilva D Rupenthal
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
| | - Jennifer P Craig
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
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16
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Guo Y, Gu D, Huang T, Li A, Zhou Y, Kang X, Meng C, Xiong D, Song L, Jiao X, Pan Z. Salmonella Enteritidis T1SS protein SiiD inhibits NLRP3 inflammasome activation via repressing the mtROS-ASC dependent pathway. PLoS Pathog 2023; 19:e1011381. [PMID: 37155697 DOI: 10.1371/journal.ppat.1011381] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/18/2023] [Accepted: 04/24/2023] [Indexed: 05/10/2023] Open
Abstract
Inflammasome activation is an essential innate immune defense mechanism against Salmonella infections. Salmonella has developed multiple strategies to avoid or delay inflammasome activation, which may be required for long-term bacterial persistence. However, the mechanisms by which Salmonella evades host immune defenses are still not well understood. In this study, Salmonella Enteritidis (SE) random insertion transposon library was screened to identify the key factors that affect the inflammasome activation. The type I secretion system (T1SS) protein SiiD was demonstrated to repress the NLRP3 inflammasome activation during SE infection and was the first to reveal the antagonistic role of T1SS in the inflammasome pathway. SiiD was translocated into host cells and localized in the membrane fraction in a T1SS-dependent and partially T3SS-1-dependent way during SE infection. Subsequently, SiiD was demonstrated to significantly suppress the generation of mitochondrial reactive oxygen species (mtROS), thus repressing ASC oligomerization to form pyroptosomes, and impairing the NLRP3 dependent Caspase-1 activation and IL-1β secretion. Importantly, SiiD-deficient SE induced stronger gut inflammation in mice and displayed NLRP3-dependent attenuation of the virulence. SiiD-mediated inhibition of NLRP3 inflammasome activation significantly contributed to SE colonization in the infected mice. This study links bacterial T1SS regulation of mtROS-ASC signaling to NLRP3 inflammasome activation and reveals the essential role of T1SS in evading host immune responses.
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Affiliation(s)
- Yaxin Guo
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
- School of Nursing School of Public Health, Yangzhou University, Jiangsu, China
| | - Dan Gu
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Tingting Huang
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Ang Li
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Yi Zhou
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Xilong Kang
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Chuang Meng
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Dan Xiong
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Li Song
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Xinan Jiao
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
| | - Zhiming Pan
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China
- Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China
- Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China
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17
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Hill C, Dellar ER, Baena‐Lopez LA. Caspases help to spread the message via extracellular vesicles. FEBS J 2023; 290:1954-1972. [PMID: 35246932 PMCID: PMC10952732 DOI: 10.1111/febs.16418] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/10/2022] [Accepted: 03/03/2022] [Indexed: 11/27/2022]
Abstract
Cell-cell communication is an essential aspect of multicellular life, key for coordinating cell proliferation, growth, and death in response to environmental changes. Whilst caspases are well-known for facilitating apoptotic and pyroptotic cell death, several recent investigations are uncovering new roles for these enzymes in biological scenarios requiring long-range intercellular signalling mediated by extracellular vesicles (EVs). EVs are small membrane-bound nanoparticles released from cells that may carry and deliver cargo between distant cells, thus helping to coordinate their behaviour. Intriguingly, there is emerging evidence indicating a key contribution of caspases in the biogenesis of EVs, the selection of their cargo content, and EV uptake/function in recipient cells. Here, we discuss the latest findings supporting the interplay between caspases and EVs, and the biological relevance of this molecular convergence for cellular signalling, principally in non-apoptotic scenarios.
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Affiliation(s)
- Claire Hill
- Sir William Dunn School of PathologyUniversity of OxfordUK
| | - Elizabeth R. Dellar
- Sir William Dunn School of PathologyUniversity of OxfordUK
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordUK
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18
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Sydor MJ, Kendall RL, Holian A. Cholesterol content regulates silica-induced lysosomal membrane permeability. FRONTIERS IN TOXICOLOGY 2023; 5:1112822. [PMID: 36860548 PMCID: PMC9969097 DOI: 10.3389/ftox.2023.1112822] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/30/2023] [Indexed: 02/15/2023] Open
Abstract
Inhalation of crystalline silica has been well documented to cause pulmonary inflammation and lung disease such as silicosis. Respirable silica particles deposit in the lungs and are phagocytosed by alveolar macrophages. Subsequently, phagocytosed silica remains undegraded within lysosomes causing lysosomal damage known as phagolysosomal membrane permeability (LMP). LMP can trigger the assembly of the NLRP3 inflammasome resulting in release of inflammatory cytokines that contribute to disease. In order to better understand the mechanisms of LMP this study used murine bone marrow derived macrophages (BMdM) as a cellular model to investigate the mechanism of silica-induced LMP. Reduction of lysosomal cholesterol in bone marrow derived macrophages with 18:1 phosphatidylglycerol (DOPG) liposome treatment increased silica-induced LMP and IL-1β release. Conversely, increasing lysosomal and cellular cholesterol with U18666A reduced IL-1β release. Co-treatment of bone marrow derived macrophages with 18:1 phosphatidylglycerol and U18666A resulted in a significant reduction of the effects of U18666A on lysosomal cholesterol. Phosphatidylcholine 100-nm liposome model systems were used to examine the effects of silica particles on lipid membrane order. Time-resolved fluorescence anisotropy of the membrane probe, Di-4-ANEPPDHQ, was used to determine changes to membrane order. Silica increased lipid order that was attenuated by inclusion of cholesterol in the phosphatidylcholine liposomes. These results demonstrate that increased cholesterol can attenuate silica-induced membrane changes in liposomes and cell models, while decreasing cholesterol exacerbates silica-induced membrane changes. Selective manipulation of lysosomal cholesterol may be a way of attenuating lysosomal disruption and preventing silica-induced chronic inflammatory disease progression.
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Affiliation(s)
- Matthew J. Sydor
- Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States
- Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT, United States
| | - Rebekah L. Kendall
- Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States
| | - Andrij Holian
- Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States
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19
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Illig D, Kotlarz D. Dysregulated inflammasome activity in intestinal inflammation - Insights from patients with very early onset IBD. Front Immunol 2022; 13:1027289. [PMID: 36524121 PMCID: PMC9744759 DOI: 10.3389/fimmu.2022.1027289] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 11/11/2022] [Indexed: 11/30/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a multifactorial disorder triggered by imbalances of the microbiome and immune dysregulations in genetically susceptible individuals. Several mouse and human studies have demonstrated that multimeric inflammasomes are critical regulators of host defense and gut homeostasis by modulating immune responses to pathogen- or damage-associated molecular patterns. In the context of IBD, excessive production of pro-inflammatory Interleukin-1β has been detected in patient-derived intestinal tissues and correlated with the disease severity or failure to respond to anti-tumor necrosis factor therapy. Correspondingly, genome-wide association studies have suggested that single nucleotide polymorphisms in inflammasome components might be associated with risk of IBD development. The relevance of inflammasomes in controlling human intestinal homeostasis has been further exemplified by the discovery of very early onset IBD (VEO-IBD) patients with monogenic defects affecting different molecules in the complex regulatory network of inflammasome activity. This review provides an overview of known causative monogenic entities of VEO-IBD associated with altered inflammasome activity. A better understanding of the molecular mechanisms controlling inflammasomes in monogenic VEO-IBD may open novel therapeutic avenues for rare and common inflammatory diseases.
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Affiliation(s)
- David Illig
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Daniel Kotlarz
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany,Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany,*Correspondence: Daniel Kotlarz,
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20
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Yang G, Kang HC, Cho YY, Lee HS, Lee JY. Inflammasomes and their roles in arthritic disease pathogenesis. Front Mol Biosci 2022; 9:1027917. [PMID: 36387275 PMCID: PMC9650081 DOI: 10.3389/fmolb.2022.1027917] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/17/2022] [Indexed: 11/14/2023] Open
Abstract
The inflammasome is a molecular platform that is created in the cytosolic compartment to mediate the host immunological response to cellular injury and infection. Caspase-1 may be activated by the inflammasome, which leads to the generation of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and the beginning of pyroptosis, which is a type of proinflammatory cell death. Scientists have identified a number of different inflammasomes in the last 2 decades. The NLRP3 inflammasome has been studied the most, and its activity may be triggered by a broad range of different inducers. However, activation of the NLRP3 inflammasome in a manner that is not properly controlled is also a factor in the etiology of many human illnesses. Accumulating evidence indicates that the NLRP3 inflammasome plays a significant role in the innate and adaptive immune systems and the development of various arthritic illnesses, such as rheumatoid arthritis, ankylosing spondylitis, and gout. The present review provides a concise summary of the biological properties of the NLRP3 inflammasome and presents the fundamental processes behind its activation and control. We discuss the role of the inflammasome in the pathogenesis of arthritic diseases, such as rheumatoid arthritis, ankylosing spondylitis, and gout, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases, with a particular emphasis on treatment and clinical application.
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Affiliation(s)
- Gabsik Yang
- Department of Pharmacology, College of Korean Medicine, Woosuk University, Jeonju, South Korea
| | - Han Chang Kang
- College of Pharmacy, The Catholic University of Korea, Seoul, South Korea
| | - Yong-Yeon Cho
- College of Pharmacy, The Catholic University of Korea, Seoul, South Korea
| | - Hye Suk Lee
- College of Pharmacy, The Catholic University of Korea, Seoul, South Korea
| | - Joo Young Lee
- College of Pharmacy, The Catholic University of Korea, Seoul, South Korea
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21
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Reus JB, Rex EA, Gammon DB. How to Inhibit Nuclear Factor-Kappa B Signaling: Lessons from Poxviruses. Pathogens 2022; 11:pathogens11091061. [PMID: 36145493 PMCID: PMC9502310 DOI: 10.3390/pathogens11091061] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/10/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
The Nuclear Factor-kappa B (NF-κB) family of transcription factors regulates key host inflammatory and antiviral gene expression programs, and thus, is often activated during viral infection through the action of pattern-recognition receptors and cytokine–receptor interactions. In turn, many viral pathogens encode strategies to manipulate and/or inhibit NF-κB signaling. This is particularly exemplified by vaccinia virus (VV), the prototypic poxvirus, which encodes at least 18 different inhibitors of NF-κB signaling. While many of these poxviral NF-κB inhibitors are not required for VV replication in cell culture, they virtually all modulate VV virulence in animal models, underscoring the important influence of poxvirus–NF-κB pathway interactions on viral pathogenesis. Here, we review the diversity of mechanisms through which VV-encoded antagonists inhibit initial NF-κB pathway activation and NF-κB signaling intermediates, as well as the activation and function of NF-κB transcription factor complexes.
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22
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Schweizer TA, Andreoni F, Acevedo C, Scheier TC, Heggli I, Maggio EM, Eberhard N, Brugger SD, Dudli S, Zinkernagel AS. Intervertebral disc cell chondroptosis elicits neutrophil response in Staphylococcus aureus spondylodiscitis. Front Immunol 2022; 13:908211. [PMID: 35967370 PMCID: PMC9366608 DOI: 10.3389/fimmu.2022.908211] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
To understand the pathophysiology of spondylodiscitis due to Staphylococcus aureus, an emerging infectious disease of the intervertebral disc (IVD) and vertebral body with a high complication rate, we combined clinical insights and experimental approaches. Clinical data and histological material of nine patients suffering from S. aureus spondylodiscitis were retrospectively collected at a single center. To mirror the clinical findings experimentally, we developed a novel porcine ex vivo model mimicking acute S. aureus spondylodiscitis and assessed the interaction between S. aureus and IVD cells within their native environment. In addition, the inflammatory features underlying this interaction were assessed in primary human IVD cells. Finally, mirroring the clinical findings, we assessed primary human neutrophils for their ability to respond to secreted inflammatory modulators of IVD cells upon the S. aureus challenge. Acute S. aureus spondylodiscitis in patients was characterized by tissue necrosis and neutrophil infiltration. Additionally, the presence of empty IVD cells’ lacunae was observed. This was mirrored in the ex vivo porcine model, where S. aureus induced extensive IVD cell death, leading to empty lacunae. Concomitant engagement of the apoptotic and pyroptotic cell death pathways was observed in primary human IVD cells, resulting in cytokine release. Among the released cytokines, functionally intact neutrophil-priming as well as broad pro- and anti-inflammatory cytokines which are known for their involvement in IVD degeneration were found. In patients as well as ex vivo in a novel porcine model, S. aureus IVD infection caused IVD cell death, resulting in empty lacunae, which was accompanied by the release of inflammatory markers and recruitment of neutrophils. These findings offer valuable insights into the important role of inflammatory IVD cell death during spondylodiscitis and potential future therapeutic approaches.
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Affiliation(s)
- Tiziano A. Schweizer
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Federica Andreoni
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Claudio Acevedo
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Thomas C. Scheier
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Irina Heggli
- Center of Experimental Rheumatology, University Hospital Zurich and Balgrist University Hospital, University of Zurich, Zurich, Switzerland
- Department of Physical Medicine and Rheumatology, University Hospital Zurich and Balgrist University Hospital, University of Zurich, Zurich, Switzerland
| | - Ewerton Marques Maggio
- Department of Pathology and Molecular Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Nadia Eberhard
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Silvio D. Brugger
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Stefan Dudli
- Center of Experimental Rheumatology, University Hospital Zurich and Balgrist University Hospital, University of Zurich, Zurich, Switzerland
- Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland
| | - Annelies S. Zinkernagel
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland
- *Correspondence: Annelies S. Zinkernagel,
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Ma X, Di Q, Li X, Zhao X, Zhang R, Xiao Y, Li X, Wu H, Tang H, Quan J, Wu Z, Xiao W, Chen W. Munronoid I Ameliorates DSS-Induced Mouse Colitis by Inhibiting NLRP3 Inflammasome Activation and Pyroptosis Via Modulation of NLRP3. Front Immunol 2022; 13:853194. [PMID: 35865528 PMCID: PMC9296101 DOI: 10.3389/fimmu.2022.853194] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/07/2022] [Indexed: 12/31/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are increasingly common diseases characterized by chronic and relapsing inflammation of the gastrointestinal tract. NLRP3 might be a crucial regulator of the homeostatic balance of the intestine, but its upregulation leads to pyroptosis. Munronoid I is extracted and purified from Munronia sinica, which has shown an anti-inflammatory effect, but the efficacy of Munronoid I in IBD remains unproven. In this study, we attempted to determine the effect of Munronoid I on NLRP3 to regulate the inflammasome activation and pyroptosis in IBD. Our data demonstrated that Munronoid I treatment attenuated DSS-induced body weight loss, pathological injury of the colon, the production of IL-1β and IL-18, and the expression of pyroptosis-associated proteins in colon tissue in mice. Moreover, Munronoid I inhibited LPS/ATP-induced pyroptosis in mouse peritoneal macrophages, MODE-K cells, and DSS-induced pyroptosis in mouse colonic epithelial cells, and decreased the release of inflammatory cytokines IL-1β and IL-18 in mouse peritoneal macrophages. Mechanically, Munronoid I could suppress the NLRP3 inflammasome activation and pyroptosis by promoting the K48-linked ubiquitination and NLRP3 degradation. It is suggested that Munronoid I might be a potential therapeutic candidate for IBD.
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Affiliation(s)
- Xingyu Ma
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Qianqian Di
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xiaoli Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
| | - Xibao Zhao
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Ruihan Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
| | - Yue Xiao
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Xunwei Li
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Han Wu
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Haimei Tang
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Jiazheng Quan
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Zherui Wu
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, China
- *Correspondence: Weilie Xiao, ; Weilin Chen,
| | - Weilin Chen
- Marshall Laboratory of Biomedical Engineering, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, China
- *Correspondence: Weilie Xiao, ; Weilin Chen,
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24
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Yue M, Xiao L, Yan R, Li X, Yang W. Pyroptosis in neurodegenerative diseases: What lies beneath the tip of the iceberg? Int Rev Immunol 2022:1-16. [PMID: 35312447 DOI: 10.1080/08830185.2022.2052064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Neurodegenerative diseases gradually receive attention with a rapidly aging global population. The hallmark of them is a progressive neuronal loss in the brain or peripheral nervous system due to complex reasons ranging from protein aggregation, immune dysregulation to abnormal cell death. The death style of nerve cell is no longer restricted to apoptosis, autophagy and necrosis as confirmed before. With the successive discoveries of the gasdermin (GSDM) protein family and key caspase molecules in the past several decades, pyroptosis emerges as a novel kind of programmed cell death. A substantial body of evidence has recognized the close connection between pyroptosis and the occurrence and development of neurodegenerative diseases. In this review, we summarize molecular mechanisms of pyroptosis, evidences for pyroptosis involvement in neurodegenerative diseases and finally we hope to provide a novel angle for clinical decision-making.
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Affiliation(s)
- Mengli Yue
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
| | - Li Xiao
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
| | - Rui Yan
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
| | - Xinyi Li
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
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25
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Wang Y, Shen X, Yin K, Miao C, Sun Y, Mao S, Liu D, Sheng J. Structural characteristics and immune-enhancing activity of fractionated polysaccharides from Athyrium Multidentatum (Doll.) Ching. Int J Biol Macromol 2022; 205:76-89. [PMID: 35181328 DOI: 10.1016/j.ijbiomac.2022.02.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 12/24/2021] [Accepted: 02/08/2022] [Indexed: 11/05/2022]
Abstract
Polysaccharides coded as CP were extracted from Athyrium Multidentatum (Doll.) Ching and then fractionated into five fractions (FP-1, FP-2, FP-3, FP-4 and FP-5). A purified polysaccharide designated as FP-3-4 was prepared from FP-3 by Sephadex G-100 column chromatography. Chemical analysis disclosed that CP and these fractions were heteropolysaccharides and mainly composed of glucose, galactose, arabinose, mannose, rhamnose, xylose, fucose, ribose and uronic acid with different molar ratios. They presented different images of SEM. FP-3-4 was highly branched polymers with sixteen types of linkages. The in vitro immunomodulatory results stated that CP and these fractions could promote macrophage proliferation, enhance macrophage phagocytosis and increase the production of NO, TNF-α, IFN-γ, IL-1β, IL-6, IL-10 and IL-2, indicating remarkable immune enhancement activities. RNA sequencing analysis revealed that CP and FP-3 induced macrophage activation mainly through MAPK and alternative NF-κΒ signaling pathways via CD14/TLR4 and Dectin-2 receptors, which were verified by RT-qPCR and western blot.
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Affiliation(s)
- Yang Wang
- Department of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Xiaoyan Shen
- Department of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Kaiyue Yin
- Department of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Changqing Miao
- Department of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Yanlong Sun
- Department of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Shumei Mao
- Department of Pharmacy, Weifang Medical University, Weifang 261053, China
| | - Dongmei Liu
- Department of Pharmacy, Weifang Medical University, Weifang 261053, China.
| | - Jiwen Sheng
- Department of Pharmacy, Weifang Medical University, Weifang 261053, China.
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26
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Naik P, Pandey S, Naik MN, Mishra DK, Boyenpally SR, Joseph J. Transcriptomic and Histological Analysis of Exacerbated Immune Response in Multidrug-Resistant Pseudomonas aeruginosa in a Murine Model of Endophthalmitis. Front Immunol 2022; 12:789023. [PMID: 35046947 PMCID: PMC8761737 DOI: 10.3389/fimmu.2021.789023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/06/2021] [Indexed: 12/30/2022] Open
Abstract
Multidrug-resistant (MDR) endophthalmitis is a serious threat to the whole spectrum of therapeutic procedures associated with the risk of managing and preventing vision loss. We have earlier shown the interplay of immune mediators in patients with MDR Pseudomonas aeruginosa (PA) endophthalmitis leading to worse outcome. Expanding on these findings, a murine model of endophthalmitis was developed to explore the effects of drug resistance on the pathogenesis by analyzing the temporal changes in retinal morphology along with its transcriptomic signatures. Clinical isolates of susceptible (S-PA) and multidrug-resistant PA (MDR-PA) were injected intravitreally in C57BL/6 mice followed by enucleation at 6 and 24 h time points postinfection. Disease progression and retinal changes were monitored by clinical and histological assessment and transcriptome analysis in a pair-wise manner. Histological assessment of MDR-PA eyeball revealed higher disease severity (p < 0.05), CD45+ cells (p = 0.007), MPO+ cells (p = 0.01), GFAP+ (p = 0.02), along with higher retinal cell death in mice infected with MDR-PA (p = 0.008). Temporal transcriptome analysis revealed differential expression of nearly 923 genes at 6 h p.i. and 2,220 genes at 24 h p.i. (FC ≥2, adjusted p-value <0.05). Pathway enrichment analysis identified differential regulation of chemokine- and cytokine-mediated, MAPK, and NF-кβ signaling pathways. In conclusion, rapid deterioration of retinal architecture and immune exacerbation was significantly associated with the MDR endophthalmitis, suggesting the need for immunomodulatory agents to strengthen host cell functions and support antibiotics to save the retinal structure from inevitable deterioration and restoration of the vision.
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Affiliation(s)
- Poonam Naik
- Jhaveri Microbiology Centre, Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India.,Center for Doctoral Studies, Manipal Academy of Higher Education, Karnataka, India
| | - Suchita Pandey
- Jhaveri Microbiology Centre, Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India
| | - Milind N Naik
- Ophthalmic Plastic Surgery & Facial Aesthetics, L V Prasad Eye Institute, Hyderabad, India
| | | | | | - Joveeta Joseph
- Jhaveri Microbiology Centre, Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India
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27
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Eiberg S, Ancker L, Javed S, Haag F. Visualizing P2X7-Dependent Inflammasome Formation in Human Monocytes by Fluorescence Microscopy and Flow Cytometry. Methods Mol Biol 2022; 2510:265-278. [PMID: 35776330 DOI: 10.1007/978-1-0716-2384-8_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
One of the most prominent effects of P2X7 activation in myeloid cells is the induction of the assembly of the NLRP3 inflammasome, a central process controlling the secretion of pro-inflammatory cytokines of the IL-1 family such as IL-1β and IL-18. The ability to visualize inflammasome formation greatly facilitates research into the role of P2X7 in inflammation. In this chapter, a method to monitor the formation of the NLPR3 inflammasome in monocytes and other myeloid cells could be demonstrated. Following priming by lipopolysaccharide (LPS), P2X7 was stimulated by ATP to mediate inflammasome assembly. This causes cytosolically disperse ASC, a central component of the inflammasome, to aggregate into microscopically visible specks due to its recruitment to the inflammasome. Methods to monitor this change in the spatial distribution of ASC in human peripheral blood monocytes by flow cytometry and fluorescence microscopy are presented.
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Affiliation(s)
- Samantha Eiberg
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Leif Ancker
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sana Javed
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Friedrich Haag
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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28
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Potential IFNγ Modulation of Inflammasome Pathway in Chlamydia trachomatis Infected Synovial Cells. Life (Basel) 2021; 11:life11121359. [PMID: 34947890 PMCID: PMC8707573 DOI: 10.3390/life11121359] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/02/2021] [Accepted: 12/04/2021] [Indexed: 01/15/2023] Open
Abstract
Following a Chlamydia trachomatis infection, the host immune response is characterized by its recognition via Toll-like and Nod-like Receptors, and the subsequent activation of interferon (IFN)-γ-mediated signaling pathways. Recently, the inflammasome-mediated host cell response has emerged to play a role in the physiopathology of C. trachomatis infection. Here we investigated, for the first time, the interaction of IFN-γ and inflammasome in an in vitro model of C. trachomatis-infected primary human synovial cells. Chlamydial replication as well as the expression of caspase-1, IL-1β, as well as IL-18 and IL-6, were assayed. Our results demonstrated the inhibitory activity of IFN-γ by interfering with the inflammasome network through the downregulation of caspase-1 mRNA expression. In addition, the ability of C. trachomatis to hinder the inflammasome pathway favoring its intracellular survival within synovial cells, was observed. Overall, our data suggest a potential mechanism of immune evasion by C. trachomatis in synovial cells, that may be contested by IFN-γ.
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29
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Koizumi M, Watanabe T, Masumoto J, Sunago K, Imamura Y, Kanemitsu K, Kumagi T, Hiasa Y. Apoptosis-associated speck-like protein containing a CARD regulates the growth of pancreatic ductal adenocarcinoma. Sci Rep 2021; 11:22351. [PMID: 34785680 PMCID: PMC8595714 DOI: 10.1038/s41598-021-01465-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 10/27/2021] [Indexed: 01/02/2023] Open
Abstract
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan-Meier Plotter. ASC expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high ASC expression in multiple PDAC cells, with ASC silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, ASC silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.
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Affiliation(s)
- Mitsuhito Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Junya Masumoto
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Ehime, Japan
| | - Kotaro Sunago
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Yoshiki Imamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Kozue Kanemitsu
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Teru Kumagi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
- Post Graduate Medical Education Center, Ehime University Hospital, Ehime, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.
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30
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Motomura K, Romero R, Garcia-Flores V, Leng Y, Xu Y, Galaz J, Slutsky R, Levenson D, Gomez-Lopez N. The alarmin interleukin-1α causes preterm birth through the NLRP3 inflammasome. Mol Hum Reprod 2021; 26:712-726. [PMID: 32647859 DOI: 10.1093/molehr/gaaa054] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/25/2020] [Indexed: 12/12/2022] Open
Abstract
Sterile intra-amniotic inflammation is a clinical condition frequently observed in women with preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Growing evidence suggests that alarmins found in amniotic fluid, such as interleukin (IL)-1α, are central initiators of sterile intra-amniotic inflammation. However, the causal link between elevated intra-amniotic concentrations of IL-1α and preterm birth has yet to be established. Herein, using an animal model of ultrasound-guided intra-amniotic injection of IL-1α, we show that elevated concentrations of IL-1α cause preterm birth and neonatal mortality. Additionally, using immunoblotting techniques and a specific immunoassay, we report that the intra-amniotic administration of IL-1α induces activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in the fetal membranes, but not in the decidua, as evidenced by a concomitant increase in the protein levels of NLRP3, active caspase-1, and IL-1β. Lastly, using Nlrp3-/- mice, we demonstrate that the deficiency of this inflammasome sensor molecule reduces the rates of preterm birth and neonatal mortality caused by the intra-amniotic injection of IL-1α. Collectively, these results demonstrate a causal link between elevated IL-1α concentrations in the amniotic cavity and preterm birth as well as adverse neonatal outcomes, a pathological process that is mediated by the NLRP3 inflammasome. These findings shed light on the mechanisms underlying sterile intra-amniotic inflammation and provide further evidence that this clinical condition can potentially be treated by targeting the NLRP3 inflammasome.
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Affiliation(s)
- K Motomura
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - R Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA.,Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.,Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.,Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.,Detroit Medical Center, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Florida International University, Miami, FL, USA
| | - V Garcia-Flores
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Y Leng
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Y Xu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - J Galaz
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - R Slutsky
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA
| | - D Levenson
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - N Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, USA and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA
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31
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Vasilev G, Manolova I, Ivanova M, Stanilov I, Miteva L, Stanilova S. The role of IL-18 in addition to Th17 cytokines in rheumatoid arthritis development and treatment in women. Sci Rep 2021; 11:15391. [PMID: 34321563 PMCID: PMC8319149 DOI: 10.1038/s41598-021-94841-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/16/2021] [Indexed: 12/31/2022] Open
Abstract
We aimed to analyze serum pro-inflammatory profiles of female rheumatoid arthritis (RA) patients and compare them with healthy women to establish the relative importance of pro-inflammatory cytokines in RA and their relation with different treatment regimens. Levels of six cytokines were determined by ELISA assays. A supervised dimensionality reducing approach (PLS-DA Analysis) was applied. All of the cytokines assayed were significantly elevated in the sera of RA female patients than healthy controls with fold change: 21-fold for IL-6; 6.1-fold for IL-17A; 2.5-fold for IL-23; 2.3-fold for IL-18; 1.94-fold for TNF-α; 1.7-fold for IL-12p40. According to the results of the PLS-DA analysis, IL-17A, IL-18, and TNF-α were of higher importance rank compared to IL-23 and IL-12p40. Women in the early stage of RA displayed significantly elevated IL-17A levels than those with longer disease duration: 8.04 pg/ml [8.04-175.3] vs 4.64 pg/ml [2.95-13.31], p = 0.007. IL-6 serum levels were related to higher disease activity. We have demonstrated altered cytokine production within female RA patients on different treatment regimens. Those on Tocilizumab therapy showed elevated IL-6 levels and decreased IL-17A versus the rest of the patients' subgroups. In conclusion, our data support the pivotal role of IL-18 in addition to IL-6, IL-17A, and TNF-α as the hierarchical cytokines in the pathogenesis of RA, particularly valid for women. Therapy with biological agents targeting IL-18 in addition to the Th17 axis may be an adequate approach in RA patients.
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Affiliation(s)
- Georgi Vasilev
- Laboratory of Clinical Immunology, University Hospital "St. Iv. Rilski", Medical University of Sofia, Sofia, Bulgaria
| | - Irena Manolova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Armeiska 11 Str, Stara Zagora, 6000, Bulgaria
| | - Mariana Ivanova
- Clinic of Rheumatology, University Hospital "St. Iv. Rilski", Medical University of Sofia, Sofia, Bulgaria
| | - Iskren Stanilov
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Armeiska 11 Str, Stara Zagora, 6000, Bulgaria
| | - Lyuba Miteva
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Armeiska 11 Str, Stara Zagora, 6000, Bulgaria.
| | - Spaska Stanilova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Armeiska 11 Str, Stara Zagora, 6000, Bulgaria
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32
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Wang Y, Zhou X, Zou K, Chen G, Huang L, Yang F, Pan W, Xu H, Xu Z, Chen H, Chen J, Gong S, Zhou X, Xu W, Zhao J. Monocarboxylate Transporter 4 Triggered Cell Pyroptosis to Aggravate Intestinal Inflammation in Inflammatory Bowel Disease. Front Immunol 2021; 12:644862. [PMID: 34093533 PMCID: PMC8170300 DOI: 10.3389/fimmu.2021.644862] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/26/2021] [Indexed: 01/17/2023] Open
Abstract
NLRP3 inflammasome has emerged as a crucial regulator of inflammatory bowel disease (IBD) characterized by a chronic inflammatory disease of the gastrointestinal tract. The expression of MCT4 is significantly increased in intestinal mucosal tissue of IBD, which has been identified to regulate intestinal barrier function. However, the function of MCT4 in cell pyroptosis remained unknown. In this study, we have established a stable cell line with MCT4 overexpression in HT-29 and CaCO2 cells, respectively. Functional analysis revealed that ectopic expression of MCT4 in CaCO2 cells contributed to cell pyroptosis as evidenced by LDH assay, which is largely attributed to Caspase-1-mediated canonical pyroptosis, but not Caspase-4 and Caspase-5, leading to cleave pro-IL-1β and IL-18 into mature form and release mediated by cleaved GSDMD. Mechanically, MCT4 overexpression in HT-29 and CaCO2 cell triggered the phosphorylation of ERK1/2 and NF-κB p65, while inhibition of MCT4 by MCT inhibitor α-Cyano-4-hydroxycinnamic acid (α-CHCA) in HT-29 and CaCO2 cells led to a significant downregulation of ERK1/2 and NF-κB activity. What’s more, blockade of ERK1/2-NF-κB pathway could reverse the promotion effect of MCT4 on IL-1β expression. Importantly, both MCT4 and Caspase-1, GSDMD were significantly increased in patients with IBD, and a positive clinical correlation between MCT4 and Caspase-1 expression was observed (p < 0.001). Taken together, these findings suggested that MCT4 promoted Caspase-1-mediated canonical cell pyroptosis to aggravate intestinal inflammation in intestinal epithelial cells (IECs) through the ERK1/2-NF-κB pathway.
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Affiliation(s)
- Yaodong Wang
- Department of Gastroenterology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, China
| | - Xiaorong Zhou
- Department of Respiratory and Critical Care, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, China
| | - Kejian Zou
- Department of General Surgery, Hainan General Hospital, Haikou, China
| | - Guanhua Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ling Huang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fangying Yang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wenxu Pan
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Hongwei Xu
- Department of Gastroenterology, Kunshan Hospital of Traditional Chinese Medicine, Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine, Kunshan, China
| | - Zhaohui Xu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Huan Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jiayu Chen
- Department of Neonatal Intensive Care Unit, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xuan Zhou
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wanfu Xu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Junhong Zhao
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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Hou ZS, Xin YR, Yang XD, Zeng C, Zhao HK, Liu MQ, Zhang MZ, Daniel JG, Li JF, Wen HS. Transcriptional Profiles of Genes Related to Stress and Immune Response in Rainbow Trout ( Oncorhynchus mykiss) Symptomatically or Asymptomatically Infected With Vibrio anguillarum. Front Immunol 2021; 12:639489. [PMID: 33968031 PMCID: PMC8097155 DOI: 10.3389/fimmu.2021.639489] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/11/2021] [Indexed: 12/29/2022] Open
Abstract
Rainbow trout (Oncorhynchus mykiss) is one of the most common aquaculture fish species worldwide. Vibriosis disease outbreaks cause significant setbacks to aquaculture. The stress and immune responses are bidirectionally modulated in response to the health challenges. Therefore, an investigation into the regulatory mechanisms of the stress and immune responses in trout is invaluable for identifying potential vibriosis treatments. We investigated the transcriptional profiles of genes associated with stress and trout immune functions after Vibrio anguillarum infection. We compared the control trout (CT, 0.9% saline injection), asymptomatic trout (AT, surviving trout with minor or no symptoms after bacteria injection), and symptomatic trout (ST, moribund trout with severe symptoms after bacteria injection). Our results showed activated immunomodulatory genes in the cytokine network and downregulated glucocorticoid and mineralocorticoid receptors in both AT and ST, indicating activation of the proinflammatory cytokine cascade as a common response in AT and ST. Moreover, the AT specifically activated the complement- and TNF-associated immune defenses in response to V. anguillarum infection. However, the complement and coagulation cascades, as well as steroid hormone homeostasis in ST, were disturbed by V. anguillarum. Our studies provide new insights toward understanding regulatory mechanisms in stress and immune functions in response to diseases.
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Affiliation(s)
- Zhi-Shuai Hou
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
| | - Yuan-Ru Xin
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
| | - Xiao-Dong Yang
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
| | - Chu Zeng
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
| | - Hong-Kui Zhao
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
| | - Meng-Qun Liu
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
| | - Mei-Zhao Zhang
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
| | - Jeffrey G Daniel
- Department of Anatomy, Physiology, and Pharmacology, Auburn University College of Veterinary Medicine, Auburn, AL, United States
| | - Ji-Fang Li
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
| | - Hai-Shen Wen
- Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Ocean University of China, Qingdao, China
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34
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Koushki K, Shahbaz SK, Mashayekhi K, Sadeghi M, Zayeri ZD, Taba MY, Banach M, Al-Rasadi K, Johnston TP, Sahebkar A. Anti-inflammatory Action of Statins in Cardiovascular Disease: the Role of Inflammasome and Toll-Like Receptor Pathways. Clin Rev Allergy Immunol 2021; 60:175-199. [PMID: 32378144 PMCID: PMC7985098 DOI: 10.1007/s12016-020-08791-9] [Citation(s) in RCA: 224] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Atherosclerosis is one type of cardiovascular disease (CVD) in which activation of the NLRP3 inflammasome and toll-like receptor (TLR) pathways is implicated. One of the most effective treatments for atherosclerosis is the use of statin medications. Recent studies have indicated that statins, in addition to their lipid-lowering effects, exert inhibitory and/or stimulatory effects on the NLRP3 inflammasome and TLRs. Some of the statins lead to activation of the inflammasome and subsequently cause secretion of IL-1β and IL-18. Thus, these actions may further aggravate the disease. On the other hand, some statins cause inhibition of the inflammasome or TLRs and along with lipid-lowering, help to improve the disease by reducing inflammation. In this article, we discuss these contradictory studies and the mechanisms of action of statins on the NLRP3 inflammasome and TLR pathways. The dose-dependent effects of statins on the NLRP3 complex are related to their chemistry, pharmacokinetic properties, and danger signals. Lipophilic statins have more pleiotropic effects on the NLRP3 complex in comparison to hydrophilic statins. Statins can suppress TLR4/MyD88/NF-ĸB signaling and cause an immune response shift to an anti-inflammatory response. Furthermore, statins inhibit the NF-ĸB pathway by decreasing the expression of TLRs 2 and 4. Statins are cost-effective drugs, which should have a continued future in the treatment of atherosclerosis due to both their immune-modulating and lipid-lowering effects.
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Affiliation(s)
- Khadijeh Koushki
- Department of Immunology, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sanaz Keshavarz Shahbaz
- Department of Immunology, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kazem Mashayekhi
- Department of Immunology, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zeinab Deris Zayeri
- Golestan Hospital Clinical Research Development Unit, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Khalid Al-Rasadi
- Medical Research Centre, Sultan Qaboos University, Muscat, Oman
- Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Lian Z, Song JX, Yu SR, Su LN, Cui YX, Li SF, Lee CY, Liang HZ, Chen H. Therapeutic targets of rosuvastatin on heart failure and associated biological mechanisms: A study of network pharmacology and experimental validation. Eur J Pharmacol 2021; 895:173888. [PMID: 33493484 DOI: 10.1016/j.ejphar.2021.173888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 11/20/2022]
Abstract
To explore the potential targets underlying the effect of rosuvastatin on heart failure (HF) by utilizing a network pharmacology approach and experiments to identify the results. PharmMapper and other databases were mined for information relevant to the prediction of rosuvastatin targets and HF-related targets. Then, the rosuvastatin-HF target gene networks were created in Cytoscape software. Eventually, the targets and enriched pathways were examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, we constructed an HF animal model and used rosuvastatin to treat them, identifying the changes in heart function and related protein expression. We further used different cells to explore the mechanisms of rosuvastatin. Thirty-five intersection targets indicated the therapeutic targets linked to HF. GO analysis showed that 481 biological processes, 4 cellular components and 23 molecular functions were identified. KEGG analysis showed 13 significant treatment pathways. In animal experiments, rosuvastatin significantly improved the cardiac function of post-myocardial infarction mice and prevented the development of HF after myocardial infarction by inhibiting IL-1Β expression. Cell experiments showed that rosuvastatin could reduce the expression of IL-1B in HUVEC and THP-1 cells. The therapeutic mechanism of rosuvastatin against HF may be closely related to the inhibition of the expression of apoptosis-related proteins, inflammatory factors, and fibrosis-related genes. However, IL-1Β is one of the most important target genes.
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Affiliation(s)
- Zheng Lian
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China
| | - Jun-Xian Song
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China
| | - Shi-Ran Yu
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China
| | - Li-Na Su
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China
| | - Yu-Xia Cui
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China
| | - Su-Fang Li
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China
| | - Chong-Yoo Lee
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China
| | - Hui-Zhu Liang
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China
| | - Hong Chen
- Department of Cardiology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People's Hospital, Beijing, China; Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China.
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36
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Boal‐Carvalho I, Mazel‐Sanchez B, Silva F, Garnier L, Yildiz S, Bonifacio JPPL, Niu C, Williams N, Francois P, Schwerk N, Schöning J, Carlens J, Viemann D, Hugues S, Schmolke M. Influenza A viruses limit NLRP3-NEK7-complex formation and pyroptosis in human macrophages. EMBO Rep 2020; 21:e50421. [PMID: 33180976 PMCID: PMC7726813 DOI: 10.15252/embr.202050421] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 10/06/2020] [Accepted: 10/09/2020] [Indexed: 12/20/2022] Open
Abstract
Pyroptosis is a fulminant form of macrophage cell death, contributing to release of pro-inflammatory cytokines. In humans, it depends on caspase 1/4-activation of gasdermin D and is characterized by the release of cytoplasmic content. Pathogens apply strategies to avoid or antagonize this host response. We demonstrate here that a small accessory protein (PB1-F2) of contemporary H5N1 and H3N2 influenza A viruses (IAV) curtails fulminant cell death of infected human macrophages. Infection of macrophages with a PB1-F2-deficient mutant of a contemporary IAV resulted in higher levels of caspase-1 activation, cleavage of gasdermin D, and release of LDH and IL-1β. Mechanistically, PB1-F2 limits transition of NLRP3 from its auto-repressed and closed confirmation into its active state. Consequently, interaction of a recently identified licensing kinase NEK7 with NLRP3 is diminished, which is required to initiate inflammasome assembly.
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Affiliation(s)
- Inês Boal‐Carvalho
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
| | - Béryl Mazel‐Sanchez
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
| | - Filo Silva
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
| | - Laure Garnier
- Department of Pathology and ImmunologyUniversity of GenevaGenevaSwitzerland
| | - Soner Yildiz
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
| | - Joao PPL Bonifacio
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
| | - Chengyue Niu
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
| | - Nathalia Williams
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
| | - Patrice Francois
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
| | - Nicolaus Schwerk
- Department of Pediatric Pneumology, Allergology and NeonatologyHannover Medical SchoolHannoverGermany
| | - Jennifer Schöning
- Department of Pediatric Pneumology, Allergology and NeonatologyHannover Medical SchoolHannoverGermany
| | - Julia Carlens
- Department of Pediatric Pneumology, Allergology and NeonatologyHannover Medical SchoolHannoverGermany
| | - Dorothee Viemann
- Department of Pediatric Pneumology, Allergology and NeonatologyHannover Medical SchoolHannoverGermany
- Cluster of Excellence RESIST (EXC 2155)Hannover Medical SchoolHannoverGermany
| | - Stephanie Hugues
- Department of Pathology and ImmunologyUniversity of GenevaGenevaSwitzerland
| | - Mirco Schmolke
- Department of Microbiology and Molecular MedicineUniversity of GenevaGenevaSwitzerland
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37
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Downs KP, Nguyen H, Dorfleutner A, Stehlik C. An overview of the non-canonical inflammasome. Mol Aspects Med 2020; 76:100924. [PMID: 33187725 PMCID: PMC7808250 DOI: 10.1016/j.mam.2020.100924] [Citation(s) in RCA: 191] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 10/30/2020] [Accepted: 11/03/2020] [Indexed: 12/21/2022]
Abstract
Inflammasomes are large cytosolic multiprotein complexes assembled in response to infection and cellular stress, and are crucial for the activation of inflammatory caspases and the subsequent processing and release of pro-inflammatory mediators. While caspase-1 is activated within the canonical inflammasome, the related caspase-4 (also known as caspase-11 in mice) and caspase-5 are activated within the non-canonical inflammasome upon sensing of cytosolic lipopolysaccharide (LPS) from Gram-negative bacteria. However, the consequences of canonical and non-canonical inflammasome activation are similar. Caspase-1 promotes the processing and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and the release of danger signals, as well as a lytic form of cell death called pyroptosis, whereas caspase-4, caspase-5 and caspase-11 directly promote pyroptosis through cleavage of the pore-forming protein gasdermin D (GSDMD), and trigger a secondary activation of the canonical NLRP3 inflammasome for cytokine release. Since the presence of the non-canonical inflammasome activator LPS leads to endotoxemia and sepsis, non-canonical inflammasome activation and regulation has important clinical ramifications. Here we discuss the mechanism of non-canonical inflammasome activation, mechanisms regulating its activity and its contribution to health and disease.
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Affiliation(s)
- Kevin P Downs
- Department of Pathology and Laboratory Medicine, Cedars Sinai, Los Angeles, CA, 90048, USA.
| | - Huyen Nguyen
- Department of Pathology and Laboratory Medicine, Cedars Sinai, Los Angeles, CA, 90048, USA.
| | - Andrea Dorfleutner
- Department of Pathology and Laboratory Medicine, Cedars Sinai, Los Angeles, CA, 90048, USA; Department of Biomedical Sciences, Cedars Sinai, Los Angeles, CA, 90048, USA.
| | - Christian Stehlik
- Department of Pathology and Laboratory Medicine, Cedars Sinai, Los Angeles, CA, 90048, USA; Department of Biomedical Sciences, Cedars Sinai, Los Angeles, CA, 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai, Los Angeles, CA, 90048, USA.
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McElvaney OJ, McEvoy NL, McElvaney OF, Carroll TP, Murphy MP, Dunlea DM, Ní Choileáin O, Clarke J, O'Connor E, Hogan G, Ryan D, Sulaiman I, Gunaratnam C, Branagan P, O'Brien ME, Morgan RK, Costello RW, Hurley K, Walsh S, de Barra E, McNally C, McConkey S, Boland F, Galvin S, Kiernan F, O'Rourke J, Dwyer R, Power M, Geoghegan P, Larkin C, O'Leary RA, Freeman J, Gaffney A, Marsh B, Curley GF, McElvaney NG. Characterization of the Inflammatory Response to Severe COVID-19 Illness. Am J Respir Crit Care Med 2020; 202:812-821. [PMID: 32584597 PMCID: PMC7491404 DOI: 10.1164/rccm.202005-1583oc] [Citation(s) in RCA: 457] [Impact Index Per Article: 91.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 06/25/2020] [Indexed: 12/22/2022] Open
Abstract
Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.
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Affiliation(s)
| | | | | | | | | | | | | | - Jennifer Clarke
- Department of Anaesthesia and Critical Care
- Beaumont Hospital, Dublin, Ireland; and
| | | | | | | | | | | | | | | | | | | | | | | | - Eoghan de Barra
- Department of International Health and Tropical Medicine, and
| | | | - Samuel McConkey
- Department of International Health and Tropical Medicine, and
| | - Fiona Boland
- Data Science Centre, Division of Biostatistics and Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | | | | | | | | | | | | | | | | | | | - Brian Marsh
- Department of Critical Care Medicine, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Gerard F Curley
- Department of Anaesthesia and Critical Care
- Beaumont Hospital, Dublin, Ireland; and
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IL-18 and related function proteins associated with tuberculosis severity and screening for active TB among patients with non-mycobacterial community-acquired pneumonia (CAP). Saudi J Biol Sci 2020; 27:3035-3045. [PMID: 33100863 PMCID: PMC7569146 DOI: 10.1016/j.sjbs.2020.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 08/31/2020] [Accepted: 09/01/2020] [Indexed: 01/04/2023] Open
Abstract
Background Differentiation of active pulmonary tuberculosis (TB) from non-mycobacterial community-acquired pneumonia (CAP) still remains a diagnostic challenge. Objective The study aimed to quantify the IL-18, IFN-γ, IL-18BP, IL-37, and IP-10 levels in serum and Mycobacterium tuberculosis (M.tb) antigens-stimulated blood cultures from TB or CAP patients and explore if the proteins can be a useful basis for discriminating these diseases. Methods In total, 124 Polish adults, including mild/moderate (M/MTB) or advanced (ATB) TB patients, and CAP patients, were enrolled in the study. The concentrations of IL-18, IL-18BP, IFN-γ, IL-37, and IP-10 in sera and M.tb-stimulated cultures were measured by ELISA. Results The most specific and sensitive serum proteins discriminating TB from CAP were IP-10 and IL-18BP; however, IP-10 had the highest AUC in the ROC curve for the diagnosis. Serum IP-10 and IL-18BP levels increased significantly in M/MTB or ATB groups. The IL-18BP elevation in ATB group was accompanied by an increase in IL-18. No single protein measured in M.tb-stimulated cultures differed TB from CAP patients. Conclusions The combined analysis of serum IL-18BP and IP-10 might be considered as an auxiliary tool in the differentiation of TB from CAP.
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Gomez-Lopez N, Romero R, Garcia-Flores V, Leng Y, Miller D, Hassan SS, Hsu CD, Panaitescu B. Inhibition of the NLRP3 inflammasome can prevent sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes†. Biol Reprod 2020; 100:1306-1318. [PMID: 30596885 DOI: 10.1093/biolre/ioy264] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/10/2018] [Accepted: 12/26/2018] [Indexed: 01/20/2023] Open
Abstract
Sterile intra-amniotic inflammation is commonly observed in patients with spontaneous preterm labor, a syndrome that commonly precedes preterm birth, the leading cause of perinatal morbidity and mortality worldwide. However, the mechanisms leading to sterile intra-amniotic inflammation are poorly understood and no treatment exists for this clinical condition. Herein, we investigated whether the alarmin S100B could induce sterile intra-amniotic inflammation by activating the NLRP3 inflammasome, and whether the inhibition of this pathway could prevent preterm labor/birth and adverse neonatal outcomes. We found that the ultrasound-guided intra-amniotic administration of S100B induced a 50% rate of preterm labor/birth and a high rate of neonatal mortality (59.7%) without altering the fetal and placental weights. Using a multiplex cytokine array and immunoblotting, we reported that S100B caused a proinflammatory response in the amniotic cavity and induced the activation of the NLRP3 inflammasome in the fetal membranes, indicated by the upregulation of the NLRP3 protein and increased release of active caspase-1 and mature IL-1β. Inhibition of the NLRP3 inflammasome via the specific inhibitor MCC950 prevented preterm labor/birth by 35.7% and reduced neonatal mortality by 26.7%. Yet, inhibition of the NLRP3 inflammasome at term did not drastically obstruct the physiological process of parturition. In conclusion, the data presented herein indicate that the alarmin S100B can induce sterile intra-amniotic inflammation, preterm labor/birth, and adverse neonatal outcomes by activating the NLRP3 inflammasome, which can be prevented by inhibiting such a pathway. These findings provide evidence that sterile intra-amniotic inflammation could be treated by targeting the NLRP3 inflammasome.
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Affiliation(s)
- Nardhy Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.,Department of Immunology, Microbiology and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Roberto Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA.,Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA.,Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA
| | - Valeria Garcia-Flores
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Yaozhu Leng
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Derek Miller
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Sonia S Hassan
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.,Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Chaur-Dong Hsu
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.,Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Bogdan Panaitescu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Faro J, Romero R, Schwenkel G, Garcia-Flores V, Arenas-Hernandez M, Leng Y, Xu Y, Miller D, Hassan SS, Gomez-Lopez N. Intra-amniotic inflammation induces preterm birth by activating the NLRP3 inflammasome†. Biol Reprod 2020; 100:1290-1305. [PMID: 30590393 DOI: 10.1093/biolre/ioy261] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 11/12/2018] [Accepted: 12/22/2018] [Indexed: 01/23/2023] Open
Abstract
Intra-amniotic inflammation is strongly associated with spontaneous preterm labor and birth, the leading cause of perinatal mortality and morbidity worldwide. Previous studies have suggested a role for the NLRP3 (NLR family pyrin domain-containing protein 3) inflammasome in the mechanisms that lead to preterm labor and birth. However, a causal link between the NLRP3 inflammasome and preterm labor/birth induced by intra-amniotic inflammation has not been established. Herein, using an animal model of lipopolysaccharide-induced intra-amniotic inflammation (IAI), we demonstrated that there was priming of the NLRP3 inflammasome (1) at the transcriptional level, indicated by enhanced mRNA expression of inflammasome-related genes (Nlrp3, Casp1, Il1b); and (2) at the protein level, indicated by greater protein concentrations of NLRP3, in both the fetal membranes and decidua basalis prior to preterm birth. Additionally, we showed that there was canonical activation of the NLRP3 inflammasome in the fetal membranes, but not in the decidua basalis, prior to IAI-induced preterm birth as evidenced by increased protein levels of active caspase-1. Protein concentrations of released IL1β were also increased in both the fetal membranes and decidua basalis, as well as in the amniotic fluid, prior to IAI-induced preterm birth. Finally, using the specific NLRP3 inhibitor, MCC950, we showed that in vivo inhibition of the NLRP3 inflammasome reduced IAI-induced preterm birth and neonatal mortality. Collectively, these results provide a causal link between NLRP3 inflammasome activation and spontaneous preterm labor and birth in the context of intra-amniotic inflammation. We also showed that, by targeting the NLRP3 inflammasome, adverse pregnancy and neonatal outcomes can be significantly reduced.
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Affiliation(s)
- Jonathan Faro
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Roberto Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA.,Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA.,Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA
| | - George Schwenkel
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Valeria Garcia-Flores
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Marcia Arenas-Hernandez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Yaozhu Leng
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Yi Xu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Derek Miller
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Sonia S Hassan
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.,Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Nardhy Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA.,Department of Immunology, Microbiology and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan, USA
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Edilova MI, Akram A, Abdul-Sater AA. Innate immunity drives pathogenesis of rheumatoid arthritis. Biomed J 2020; 44:172-182. [PMID: 32798211 PMCID: PMC8178572 DOI: 10.1016/j.bj.2020.06.010] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the general population. This disease is characterized by persistent articular inflammation and joint damage driven by the proliferating synovial tissue fibroblasts as well as neutrophil, monocyte and lymphocyte trafficking into the synovium. The factors leading to RA pathogenesis remain poorly elucidated although genetic and environmental factors have been proposed to be the main contributors to RA. The majority of the early studies focused on the role of lymphocytes and adaptive immune responses in RA. However, in the past two decades, emerging studies showed that the innate immune system plays a critical role in the onset and progression of RA pathogenesis. Various innate immune cells including monocytes, macrophages and dendritic cells are involved in inflammatory responses seen in RA patients as well as in driving the activation of the adaptive immune system, which plays a major role in the later stages of the disease. Here we focus the discussion on the role of different innate immune cells and components in initiation and progression of RA. New therapeutic approaches targeting different inflammatory pathways and innate immune cells will be highlighted here. Recent emergence and the significant roles of innate lymphoid cells and inflammasomes will be also discussed.
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Affiliation(s)
- Maria I Edilova
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Ali Akram
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, Ontario Canada; The University Health Network, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Ali A Abdul-Sater
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, Ontario Canada.
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Bezold V, Rosenstock P, Scheffler J, Geyer H, Horstkorte R, Bork K. Glycation of macrophages induces expression of pro-inflammatory cytokines and reduces phagocytic efficiency. Aging (Albany NY) 2020; 11:5258-5275. [PMID: 31386629 PMCID: PMC6682540 DOI: 10.18632/aging.102123] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/21/2019] [Indexed: 02/06/2023]
Abstract
Glycation and the accumulation of advanced glycation end products (AGEs) are known to occur during normal aging but also in the progression of several diseases, such as diabetes. Diabetes type II and aging both lead to impaired wound healing. It has been demonstrated that macrophages play an important role in impaired wound healing, however, the underlying causes remain unknown. Elevated blood glucose levels as well as elevated methylglyoxal (MGO) levels in diabetic patients result in glycation and increase of AGEs. We used MGO to investigate the influence of glycation and AGEs on macrophages. We could show that glycation, but not treatment with AGE-modified serum proteins, increased expression of pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-8 but also affected IL-10 and TNF-α expression, resulting in increased inflammation. At the same time, glycation reduced phagocytic efficiency and led to impaired clearance rates of invading microbes and cellular debris. Our data suggest that glycation contributes to changes of macrophage activity and cytokine expression and therefore could support the understanding of disturbed wound healing during aging and diabetes.
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Affiliation(s)
- Veronika Bezold
- Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Philip Rosenstock
- Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Jonas Scheffler
- Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Henriette Geyer
- Octapharma Biopharmaceuticals GmbH, Molecular Biochemistry, Berlin, Germany
| | - Rüdiger Horstkorte
- Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Kaya Bork
- Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
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Christgen S, Place DE, Kanneganti TD. Toward targeting inflammasomes: insights into their regulation and activation. Cell Res 2020; 30:315-327. [PMID: 32152420 PMCID: PMC7118104 DOI: 10.1038/s41422-020-0295-8] [Citation(s) in RCA: 194] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 02/20/2020] [Indexed: 11/27/2022] Open
Abstract
Inflammasomes are multi-component signaling complexes critical to the initiation of pyroptotic cell death in response to invading pathogens and cellular damage. A number of innate immune receptors have been reported to serve as inflammasome sensors. Activation of these sensors leads to the proteolytic activation of caspase-1, a proinflammatory caspase responsible for the cleavage of proinflammatory cytokines interleukin-1β and interleukin-18 and the effector of pyroptotic cell death, gasdermin D. Though crucial to the innate immune response to infection, dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. Therefore, clinical interest in the modulation of inflammasome activation is swiftly growing. As such, it is imperative to develop a mechanistic understanding of the regulation of these complexes. In this review, we divide the regulation of inflammasome activation into three parts. We discuss the transcriptional regulation of inflammasome components and related proteins, the post-translational mechanisms of inflammasome activation, and advances in the understanding of the structural basis of inflammasome activation.
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Affiliation(s)
- Shelbi Christgen
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - David E Place
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
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Arita Y, Yoshinaga Y, Kaneko T, Kawahara Y, Nakamura K, Ohgi K, Arita S, Ryu T, Takase M, Sakagami R. Glyburide inhibits the bone resorption induced by traumatic occlusion in rats. J Periodontal Res 2020; 55:464-471. [PMID: 32153049 DOI: 10.1111/jre.12731] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 11/25/2019] [Accepted: 12/28/2019] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To examine whether glyburide inhibits bone destruction caused by traumatic occlusion in a rat occlusal trauma model. BACKGROUND Excessive mechanical stress, such as traumatic occlusion, induces expression of IL-1β and may be involved in bone resorption. NLRP3 inflammasomes have been linked to IL-1β expression, but it is currently unclear whether glyburide, the inhibiter of NLRP3 inflammasome, suppresses occlusal trauma in rats. METHODS Male SD rats aged 7 weeks were used. In the trauma group, the occlusal surface of the maxillary first right molar was raised by attaching a metal wire to apply occlusal trauma to the mandibular first right molar. In the trauma + glyburide group, the NLRP3 inhibitor glyburide was administered orally every 24 hours from 1 day before induction of occlusal trauma. Rats were euthanized after 5 or 10 days, and the maxillary first molars were harvested with the adjacent tissues for histopathological investigation. Immunohistochemical expression of IL-1β, NLRP3, and RANKL was also assessed. RESULTS On day 5, bone resorption was significantly greater in the trauma group compared with the control group or the trauma + glyburide group, and there were significantly higher numbers of osteoclasts and cells positive for IL-1β, NLRP3, and RANKL in the trauma group. CONCLUSION In this study, glyburide inhibits bone resorption by traumatic occlusion in rats. It suggests that the NLRP3/IL-1β pathway might be associated with bone resorption induced by traumatic occlusion.
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Affiliation(s)
- Yoichi Arita
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
| | - Yasunori Yoshinaga
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan.,Oral Medicine Research Center, Fukuoka Dental College, Fukuoka, Japan
| | - Takashi Kaneko
- Center for Oral Diseases, Fukuoka Dental College, Fukuoka, Japan
| | - Yuri Kawahara
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
| | - Keiko Nakamura
- Center for Oral Diseases, Fukuoka Dental College, Fukuoka, Japan
| | - Kimiko Ohgi
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
| | - Seiichi Arita
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
| | - Takanori Ryu
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
| | - Minoru Takase
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
| | - Ryuji Sakagami
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
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Theis KR, Romero R, Motomura K, Galaz J, Winters AD, Pacora P, Miller D, Slutsky R, Florova V, Levenson D, Para R, Varrey A, Kacerovsky M, Hsu CD, Gomez-Lopez N. Microbial burden and inflammasome activation in amniotic fluid of patients with preterm prelabor rupture of membranes. J Perinat Med 2020; 48:115-131. [PMID: 31927525 PMCID: PMC7147952 DOI: 10.1515/jpm-2019-0398] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 12/01/2019] [Indexed: 02/07/2023]
Abstract
Background Intra-amniotic inflammation, which is associated with adverse pregnancy outcomes, can occur in the presence or absence of detectable microorganisms, and involves activation of the inflammasome. Intra-amniotic inflammasome activation has been reported in clinical chorioamnionitis at term and preterm labor with intact membranes, but it has not yet been investigated in women with preterm prelabor rupture of membranes (preterm PROM) in the presence/absence of detectable microorganisms. The aim of this study was to determine whether, among women with preterm PROM, there is an association between detectable microorganisms in amniotic fluid and intra-amniotic inflammation, and whether intra-amniotic inflammasome activation correlates with microbial burden. Methods Amniotic fluids from 59 cases of preterm PROM were examined for the presence/absence of microorganisms through culture and 16S ribosomal RNA (rRNA) gene quantitative real-time polymerase chain reaction (qPCR), and concentrations of interleukin-6 (IL-6) and ASC [apoptosis-associated spec-like protein containing a caspase recruitment domain (CARD)], an indicator of inflammasome activation, were determined. Results qPCR identified more microbe-positive amniotic fluids than culture. Greater than 50% of patients with a negative culture and high IL-6 concentration in amniotic fluid yielded a positive qPCR signal. ASC concentrations were greatest in patients with high qPCR signals and elevated IL-6 concentrations in amniotic fluid (i.e. intra-amniotic infection). ASC concentrations tended to increase in patients without detectable microorganisms but yet with elevated IL-6 concentrations (i.e. sterile intra-amniotic inflammation) compared to those without intra-amniotic inflammation. Conclusion qPCR is a valuable complement to microbiological culture for the detection of microorganisms in the amniotic cavity in women with preterm PROM, and microbial burden is associated with the severity of intra-amniotic inflammatory response, including inflammasome activation.
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Affiliation(s)
- Kevin R. Theis
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Roberto Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA
- Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA
- Detroit Medical Center, Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Florida International University, Miami, Florida, USA
| | - Kenichiro Motomura
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Jose Galaz
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andrew D. Winters
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Percy Pacora
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Derek Miller
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Rebecca Slutsky
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
| | - Violetta Florova
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Dustyn Levenson
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Robert Para
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Aneesha Varrey
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Marian Kacerovsky
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Chaur-Dong Hsu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
- Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Nardhy Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Gomez-Lopez N, Romero R, Leng Y, Xu Y, Slutsky R, Levenson D, Pacora P, Jung E, Panaitescu B, Hsu CD. The origin of amniotic fluid monocytes/macrophages in women with intra-amniotic inflammation or infection. J Perinat Med 2019; 47:822-840. [PMID: 31494640 PMCID: PMC7062293 DOI: 10.1515/jpm-2019-0262] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 08/15/2019] [Indexed: 12/24/2022]
Abstract
Background Monocytes, after neutrophils, are the most abundant white blood cells found in the amniotic cavity of women with intra-amniotic inflammation/infection. However, the origin of such cells has not been fully investigated. Herein, we determined (1) the origin of amniotic fluid monocytes/macrophages from women with intra-amniotic inflammation/infection, (2) the relationship between the origin of amniotic fluid monocytes/macrophages and preterm or term delivery and (3) the localization of monocytes/macrophages in the placental tissues. Methods Amniotic fluid samples (n = 16) were collected from women with suspected intra-amniotic inflammation or infection. Amniotic fluid monocytes/macrophages were purified by fluorescence-activated cell sorting, and DNA fingerprinting was performed. Blinded placental histopathological evaluations were conducted. Immunohistochemistry was performed to detect CD14+ monocytes/macrophages in the placental tissues. Results DNA fingerprinting revealed that (1) 56.25% (9/16) of amniotic fluid samples had mostly fetal monocytes/macrophages, (2) 37.5% (6/16) had predominantly maternal monocytes/macrophages and (3) one sample (6.25% [1/16]) had a mixture of fetal and maternal monocytes/macrophages. (4) Most samples with predominantly fetal monocytes/macrophages were from women who delivered early preterm neonates (77.8% [7/9]), whereas all samples with mostly maternal monocytes/macrophages or a mixture of both were from women who delivered term or late preterm neonates (100% [7/7]). (5) Most of the women included in this study presented acute maternal and fetal inflammatory responses in the placenta (85.7% [12/14]). (6) Women who had mostly fetal monocytes/macrophages in amniotic fluid had abundant CD14+ cells in the umbilical cord and chorionic plate, whereas women with mostly maternal amniotic fluid monocytes/macrophages had abundant CD14+ cells in the chorioamniotic membranes. Conclusion Amniotic fluid monocytes/macrophages can be of either fetal or maternal origin, or a mixture of both, in women with intra-amniotic inflammation or infection. These immune cells could be derived from the fetal and maternal vasculature of the placenta.
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Affiliation(s)
- Nardhy Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA,Department of Immunology, Microbiology and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Roberto Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA,Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA,Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA,Detroit Medical Center, Detroit, Michigan, USA
| | - Yaozhu Leng
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Yi Xu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Rebecca Slutsky
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA
| | - Dustyn Levenson
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Percy Pacora
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Eunjung Jung
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Bogdan Panaitescu
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Chaur-Dong Hsu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USA,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA,Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA
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Lipinski S, Pfeuffer S, Arnold P, Treitz C, Aden K, Ebsen H, Falk-Paulsen M, Gisch N, Fazio A, Kuiper J, Luzius A, Billmann-Born S, Schreiber S, Nuñez G, Beer HD, Strowig T, Lamkanfi M, Tholey A, Rosenstiel P. Prdx4 limits caspase-1 activation and restricts inflammasome-mediated signaling by extracellular vesicles. EMBO J 2019; 38:e101266. [PMID: 31544965 PMCID: PMC6792017 DOI: 10.15252/embj.2018101266] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 08/05/2019] [Accepted: 08/21/2019] [Indexed: 12/15/2022] Open
Abstract
Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL‐1β by proteolytic cleavage via caspase‐1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasome‐dependent immune responses remain poorly defined. Here, we show that the thiol‐specific peroxidase peroxiredoxin‐4 (Prdx4) directly regulates IL‐1β generation by interfering with caspase‐1 activity. We demonstrate that caspase‐1 and Prdx4 form a redox‐sensitive regulatory complex via caspase‐1 cysteine 397 that leads to caspase‐1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPS‐induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4‐ΔLysMCre). Strikingly, we demonstrate that Prdx4 co‐localizes with inflammasome components in extracellular vesicles (EVs) from inflammasome‐activated macrophages. Purified EVs are able to transmit a robust IL‐1β‐dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the pro‐inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cell‐to‐cell communication function of inflammasomes via macrophage‐derived EVs.
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Affiliation(s)
- Simone Lipinski
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Steffen Pfeuffer
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Philipp Arnold
- Anatomical Institute, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Christian Treitz
- Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Konrad Aden
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.,1st Department of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Henriette Ebsen
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Maren Falk-Paulsen
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Nicolas Gisch
- Division of Bioanalytical Chemistry, Priority Area Infections, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Antonella Fazio
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Jan Kuiper
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Anne Luzius
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Susanne Billmann-Born
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Stefan Schreiber
- 1st Department of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Gabriel Nuñez
- Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Hans-Dietmar Beer
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Till Strowig
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Mohamed Lamkanfi
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
| | - Andreas Tholey
- Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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Gomez-Lopez N, Romero R, Tarca AL, Miller D, Panaitescu B, Schwenkel G, Gudicha DW, Hassan SS, Pacora P, Jung E, Hsu CD. Gasdermin D: Evidence of pyroptosis in spontaneous preterm labor with sterile intra-amniotic inflammation or intra-amniotic infection. Am J Reprod Immunol 2019; 82:e13184. [PMID: 31461796 DOI: 10.1111/aji.13184] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 08/19/2019] [Accepted: 08/22/2019] [Indexed: 12/29/2022] Open
Abstract
PROBLEM Pyroptosis, inflammatory programmed cell death, is initiated through the inflammasome and relies on the pore-forming actions of the effector molecule gasdermin D. Herein, we investigated whether gasdermin D is detectable in women with spontaneous preterm labor and sterile intra-amniotic inflammation or intra-amniotic infection. METHOD OF STUDY Amniotic fluid samples (n = 124) from women with spontaneous preterm labor were subdivided into the following groups: (a) those who delivered at term (n = 32); and those who delivered preterm (b) without intra-amniotic inflammation (n = 41), (c) with sterile intra-amniotic inflammation (n = 32), or (d) with intra-amniotic infection (n = 19), based on amniotic fluid IL-6 concentrations and the microbiological status of amniotic fluid (culture and PCR/ESI-MS). Gasdermin D concentrations were measured using an ELISA kit. Multiplex immunofluorescence staining was also performed to determine the expression of gasdermin D, caspase-1, and interleukin-1β in the chorioamniotic membranes. Flow cytometry was used to detect pyroptosis (active caspase-1) in decidual cells from women with preterm labor and birth. RESULTS (a) Gasdermin D was detected in the amniotic fluid and chorioamniotic membranes from women who underwent spontaneous preterm labor/birth with either sterile intra-amniotic inflammation or intra-amniotic infection, but was rarely detected in those without intra-amniotic inflammation. (b) Amniotic fluid concentrations of gasdermin D were higher in women with intra-amniotic infection than in those with sterile intra-amniotic inflammation, and its expression in the chorioamniotic membranes was associated with caspase-1 and IL-1β (inflammasome mediators). (c) Decidual stromal cells and leukocytes isolated from women with preterm labor and birth are capable of undergoing pyroptosis given their expression of active caspase-1. CONCLUSION Pyroptosis can occur in the context of sterile intra-amniotic inflammation and intra-amniotic infection in patients with spontaneous preterm labor and birth.
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Affiliation(s)
- Nardhy Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Immunology, Microbiology and Biochemistry, Wayne State University School of Medicine, Detroit, MI, USA
| | - Roberto Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.,Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.,Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.,Detroit Medical Center, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Florida International University, Miami, FL, USA
| | - Adi L Tarca
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Computer Science, Wayne State University College of Engineering, Detroit, MI, USA
| | - Derek Miller
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Bogdan Panaitescu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - George Schwenkel
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Dereje W Gudicha
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Sonia S Hassan
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Percy Pacora
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Eunjung Jung
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Chaur-Dong Hsu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
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50
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Gomez-Lopez N, Romero R, Galaz J, Xu Y, Panaitescu B, Slutsky R, Motomura K, Gill N, Para R, Pacora P, Jung E, Hsu CD. Cellular immune responses in amniotic fluid of women with preterm labor and intra-amniotic infection or intra-amniotic inflammation. Am J Reprod Immunol 2019; 82:e13171. [PMID: 31323170 DOI: 10.1111/aji.13171] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 07/05/2019] [Accepted: 07/15/2019] [Indexed: 12/12/2022] Open
Abstract
PROBLEM Preterm birth is commonly preceded by preterm labor, a syndrome that is causally linked to both intra-amniotic infection and intra-amniotic inflammation. However, the stereotypical cellular immune responses in these two clinical conditions are poorly understood. METHOD OF STUDY Amniotic fluid samples (n = 26) were collected from women diagnosed with preterm labor and intra-amniotic infection (amniotic fluid IL-6 concentrations ≥2.6 ng/mL and culturable microorganisms, n = 10) or intra-amniotic inflammation (amniotic fluid IL-6 concentrations ≥2.6 ng/mL without culturable microorganisms, n = 16). Flow cytometry was performed to evaluate the phenotype and number of amniotic fluid leukocytes. Amniotic fluid concentrations of classical pro-inflammatory cytokines, type 1 and type 2 cytokines, and T-cell chemokines were determined using immunoassays. RESULTS Women with spontaneous preterm labor and intra-amniotic infection had (a) a greater number of total leukocytes, including neutrophils and monocytes/macrophages, in amniotic fluid; (b) a higher number of total T cells and CD4+ T cells, but not CD8+ T cells or B cells, in amniotic fluid; and (c) increased amniotic fluid concentrations of IL-6, IL-1β, and IL-10, compared to those with intra-amniotic inflammation. However, no differences in amniotic fluid concentrations of T-cell cytokines and chemokines were observed between these two clinical conditions. CONCLUSION The cellular immune responses observed in women with preterm labor and intra-amniotic infection are more severe than in those with intra-amniotic inflammation, and neutrophils, monocytes/macrophages, and CD4+ T cells are the main immune cells responding to microorganisms that invade the amniotic cavity. These findings provide insights into the intra-amniotic immune mechanisms underlying the human syndrome of preterm labor.
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Affiliation(s)
- Nardhy Gomez-Lopez
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Immunology, Microbiology and Biochemistry, Wayne State University School of Medicine, Detroit, MI, USA
| | - Roberto Romero
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.,Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.,Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.,Detroit Medical Center, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Florida International University, Miami, FL, USA
| | - Jose Galaz
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Yi Xu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Bogdan Panaitescu
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Rebecca Slutsky
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA
| | - Kenichiro Motomura
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Navleen Gill
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Robert Para
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Percy Pacora
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Eunjung Jung
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Chaur-Dong Hsu
- Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
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