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Wang H, Ma L, Su W, Liu Y, Xie N, Liu J. NLRP3 inflammasome in health and disease (Review). Int J Mol Med 2025; 55:48. [PMID: 39930811 PMCID: PMC11781521 DOI: 10.3892/ijmm.2025.5489] [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: 09/19/2024] [Accepted: 12/16/2024] [Indexed: 02/13/2025] Open
Abstract
Activation of inflammasomes is the activation of inflammation‑related caspase mediated by the assembly signal of multi‑protein complex and the maturity of inflammatory factors, such as IL‑1β and IL‑18. Among them, the Nod‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied type of inflammatory corpuscle at present, which is involved in the occurrence and development of numerous human diseases. Therefore, targeting the NLRP3 inflammasome has become the focus of drug development for related diseases. In this paper, the research progress of the NLRP3 inflammasome in recent years is summarized, including the activation and regulation of NLRP3 and its association with diseases. A deep understanding of the regulatory mechanism of NLRP3 will be helpful to the discovery of new drug targets and the development of therapeutic drugs.
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Affiliation(s)
- Haoran Wang
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Li Ma
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Weiran Su
- Department of Internal Medicine, Jiading District Central Hospital, Shanghai 201800, P.R. China
| | - Yangruoyu Liu
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Ning Xie
- Department of Orthopaedics, Tongji Hospital Affiliated to Tongji University, Shanghai 200065, P.R. China
| | - Jun Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
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2
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Kronsten VT, Shawcross DL. Clinical Implications of Inflammation in Patients With Cirrhosis. Am J Gastroenterol 2025; 120:65-74. [PMID: 39194320 PMCID: PMC11676607 DOI: 10.14309/ajg.0000000000003056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Abstract
Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.
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Affiliation(s)
- Victoria T. Kronsten
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London
| | - Debbie L. Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London
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3
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Kwak H, Lee E, Karki R. DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects. Immunol Rev 2025; 329:e13382. [PMID: 39158380 PMCID: PMC11744256 DOI: 10.1111/imr.13382] [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] [Indexed: 08/20/2024]
Abstract
DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights the involvement of DNA sensors in metabolic and cardiovascular diseases. Elevated levels of modified, damaged, or ectopically localized self-DNA and non-self-DNA have been observed in patients and animal models with obesity, diabetes, fatty liver disease, and cardiovascular disease. The accumulation of cytosolic DNA aberrantly activates DNA signaling pathways, driving the pathological progression of these disorders. This review highlights the roles of specific DNA sensors, such as cyclic AMP-GMP synthase and stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9), interferon gamma-inducible protein 16 (IFI16), DNA-dependent protein kinase (DNA-PK), and DEAD-box helicase 41 (DDX41) in various metabolic disorders. We explore how DNA signaling pathways in both immune and non-immune cells contribute to the development of these diseases. Furthermore, we discuss the intricate interplay between metabolic stress and immune responses, offering insights into potential therapeutic targets for managing metabolic and cardiovascular disorders. Understanding the mechanisms of DNA sensor signaling in these contexts provides a foundation for developing novel interventions aimed at mitigating the impact of these pervasive health issues.
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Affiliation(s)
- Hyosang Kwak
- Department of Biological Sciences, College of Natural ScienceSeoul National UniversitySeoulSouth Korea
| | - Ein Lee
- Department of Biomedical Sciences, College of MedicineSeoul National UniversitySeoulSouth Korea
| | - Rajendra Karki
- Department of Biological Sciences, College of Natural ScienceSeoul National UniversitySeoulSouth Korea
- Nexus Institute of Research and Innovation (NIRI)KathmanduNepal
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Taru V, Szabo G, Mehal W, Reiberger T. Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation. J Hepatol 2024; 81:895-910. [PMID: 38908436 PMCID: PMC11881887 DOI: 10.1016/j.jhep.2024.06.016] [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: 02/18/2024] [Revised: 05/23/2024] [Accepted: 06/17/2024] [Indexed: 06/24/2024]
Abstract
Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting in liver fibrosis, cirrhosis, portal hypertension and liver failure. Thus, an improved understanding of inflammasomes - as key molecular drivers of liver injury - may result in the development of novel diagnostic or prognostic biomarkers and effective therapeutics. In liver disease, innate immune cells respond to hepatic insults by activating cell-intrinsic inflammasomes via toll-like receptors and NF-κB, and by releasing pro-inflammatory cytokines (such as IL-1β, IL-18, TNF-α and IL-6). Subsequently, cells of the adaptive immune system are recruited to fuel hepatic inflammation and hepatic parenchymal cells may undergo gasdermin D-mediated programmed cell death, termed pyroptosis. With liver disease progression, there is a shift towards a type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation may also occur at extrahepatic sites, such as the white adipose tissue in MASH (metabolic dysfunction-associated steatohepatitis). In end-stage liver disease, flares of inflammation (e.g., in severe alcohol-related hepatitis) that spark on a dysfunctional immune system, contribute to inflammasome-mediated liver injury and potentially result in organ dysfunction/failure, as seen in ACLF (acute-on-chronic liver failure). This review provides an overview of current concepts regarding inflammasome activation in liver disease progression, with a focus on related biomarkers and therapeutic approaches that are being developed for patients with liver disease.
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Affiliation(s)
- Vlad Taru
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Iuliu Hatieganu University of Medicine and Pharmacy, 4(th) Dept. of Internal Medicine, Cluj-Napoca, Romania
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Wajahat Mehal
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA; West Haven Veterans Medical Center, West Haven, CT, USA.
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine (CeMM) of the Austrian Academy of Science, Vienna, Austria
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5
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Rodríguez-Negrete EV, Gálvez-Martínez M, Sánchez-Reyes K, Fajardo-Felix CF, Pérez-Reséndiz KE, Madrigal-Santillán EO, Morales-González Á, Morales-González JA. Liver Cirrhosis: The Immunocompromised State. J Clin Med 2024; 13:5582. [PMID: 39337069 PMCID: PMC11432654 DOI: 10.3390/jcm13185582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
Systemic inflammation and immunodeficiency are important components of cirrhosis-associated immune dysfunction (CAID), the severity of which is dynamic, progressive, and associated with the greater deterioration of liver function. Two inflammation phenotypes have been described: low-grade and high-grade systemic inflammation. Both of these phenotypes are related to liver cirrhosis function; thus, high-grade inflammation is correlated with the severity of hepatic insufficiency, bacterial translocation, and organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation (BT) plays a relevant role in persistent systemic inflammation in patients with cirrhosis, and the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.
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Affiliation(s)
- Elda Victoria Rodríguez-Negrete
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Marisol Gálvez-Martínez
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | - Karina Sánchez-Reyes
- Servicio de Cirugía General, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico;
| | - Carlos Fernando Fajardo-Felix
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | - Karla Erika Pérez-Reséndiz
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | | | - Ángel Morales-González
- Escuela Superior de Cómputo, Instituto Politécnico Nacional, Unidad Profesional “A. López Mateos”, Ciudad de México 07738, Mexico
| | - José Antonio Morales-González
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
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Sha X, Ye H, Wang X, Xu Z, Sun A, Xiao W, Zhang T, Yang S, Yang H. GSDMD mediated pyroptosis induced inflammation of Graves' orbitopathy via the NF-κB/ AIM2/ Caspase-1 pathway. Exp Eye Res 2024; 240:109812. [PMID: 38342335 DOI: 10.1016/j.exer.2024.109812] [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: 09/14/2023] [Revised: 12/28/2023] [Accepted: 01/28/2024] [Indexed: 02/13/2024]
Abstract
Gasdermin D (GSDMD) is a key executor which triggers pyroptosis as well as an attractive checkpoint in various inflammatory and autoimmune diseases but it has yet to prove its function in Graves'orbitopathy (GO). Our aim was to investigate GSDMD levels in orbital connective tissue and serum of GO patients and then assess the association between serum levels and patients' clinical activity score (CAS). Further, GSDMD-mediated pyroptosis and the underlying mechanism in inflammatory pathogenesis in the cultured orbital fibroblasts (OFs) of GO patients were examined. OFs were collected after tumor necrosis factor (TNF)-α or interferon (IFN)-γ treatment or combination treatment at different times, and the expression of GSDMD and related molecular mechanisms were analyzed. Then, we constructed the GSDMD knockout system with siRNA and the system was further exposed to the medium with or without IFN-γ and TNF-α for a specified time. Finally, we evaluated the production of interleukin (IL)-1β and IL-18. We found that serum GSDMD levels were elevated and positively correlated with the CAS in GO patients. Meanwhile, the expression of GSDMD and N-terminal domain (NT-GSDMD) in orbital connective tissue of GO patients was augmented. Also, increased expression of GSDMD and related pyroptosis factors was observed in vitro model of GO. We further demonstrated that GSDMD-mediated pyroptosis induced inflammation via the nuclear factor kB (NF-κB)/absent in melanoma-2 (AIM-2)/caspase-1 pathway. In addition, blocking GSDMD suppressed proinflammatory cytokine production in GO. We concluded that GSDMD may be a biomarker as well as a potential target for the evaluation and treatment of inflammation related with GO.
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Affiliation(s)
- Xiaotong Sha
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Huijing Ye
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
| | - Xing Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Zhihui Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Anqi Sun
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Wei Xiao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Te Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Shenglan Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Huasheng Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
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You G, Zheng L, Zhang Y, Zhang Y, Wang Y, Guo W, Liu H, Tatiana P, Vladimir K, Zan J. Tangeretin Attenuates Cerebral Ischemia-Reperfusion-Induced Neuronal Pyroptosis by Inhibiting AIM2 Inflammasome Activation via Regulating NRF2. Inflammation 2024; 47:145-158. [PMID: 37725272 DOI: 10.1007/s10753-023-01900-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/27/2023] [Accepted: 09/05/2023] [Indexed: 09/21/2023]
Abstract
Pyroptosis is closely involved in the pathopoiesis of cerebral ischemia and reperfusion (I/R) injury which seriously dangers human's life. Studies report that tangeretin (TANG), which is enriched in the peel of Citrus reticulata, has neuroprotective effects. Here, we explored whether absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis is involved in the cerebral I/R injury and the protective mechanism of TANG against cerebral I/R injury. In this study, we found that TANG treatment effectively alleviated I/R-induced brain injury and inhibited neuronal pyroptosis in an in vivo mice model with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and in an in vitro hippocampal HT22 cell model with oxygen-glucose deprivation and reoxygenation (OGD/R) injury. Furthermore, we found TANG inhibited cerebral I/R-induced neuronal AIM2 inflammasome activation in vivo and in vitro via regulating nuclear factor E2-related factor 2 (NRF2). Moreover, administration of ML385, a chemical inhibitor of NRF2, notably blocked the neuroprotective effects of TANG against cerebral I/R injury. In conclusion, TANG attenuates cerebral I/R-induced neuronal pyroptosis by inhibiting AIM2 inflammasome activation via regulating NRF2. These findings indicate TANG is a potential therapeutic agent for cerebral I/R injury.
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Affiliation(s)
- Guoxing You
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Linbo Zheng
- Department of Traditional Chinese Medicine, Guangdong Second Provincial General Hospital, Guangzhou, 510310, China
| | - Yuanyuan Zhang
- The Affiliated Traditional Chinese Medicine Hospital of Guangzhou Medical University, Guangzhou, 510130, China
| | - Yuting Zhang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Yupeng Wang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Wenjie Guo
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China
| | - Hao Liu
- Department of Traditional Chinese Medicine, Guangdong Second Provincial General Hospital, Guangzhou, 510310, China
| | - Philipovich Tatiana
- Institute of Physiology, National Academy of Sciences of Belarus, Minsk, 220072, Republic of Belarus
| | - Kulchitsky Vladimir
- Institute of Physiology, National Academy of Sciences of Belarus, Minsk, 220072, Republic of Belarus
| | - Jie Zan
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China.
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He W, Xu C, Mao D, Zheng Y, Wang N, Wang M, Mao N, Wang T, Li Y. Recent advances in pyroptosis, liver disease, and traditional Chinese medicine: A review. Phytother Res 2023; 37:5473-5494. [PMID: 37622684 DOI: 10.1002/ptr.7989] [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: 03/28/2023] [Revised: 07/29/2023] [Accepted: 08/09/2023] [Indexed: 08/26/2023]
Abstract
In recent years, the incidence of liver disease has increased, becoming a major cause of death. Various liver diseases are intricately linked to pyroptosis, which is one of the most common forms of programmed cell death. As a powerful weapon in the fight against liver diseases, traditional Chinese medicine (TCM) can affect pyroptosis via a number of routes, including the classical, nucleotide oligomerization domain-like receptors protein 3/caspase-1/gasdermin D (GSDMD) pathway, the nonclassical lipopolysaccharide/caspase-11/GSDMD pathway, the ROS/caspase-3/gasdermin E pathway, the caspase-9/caspase-3/GSDMD pathway, and the Apaf-1/caspase-11/caspase-3 pathway. In this review, we provide an overview of pyroptosis, the interplay between pyroptosis and liver diseases, and the mechanisms through which TCM regulates pyroptosis in liver diseases. The information used in the text was collected and compiled from the databases of PubMed, Web of Science, Scopus, CNKI, and Wanfang Data up to June 2023. The search was not limited with regard to the language and country of the articles. Research and review articles were included, and papers with duplicate results or unrelated content were excluded. We examined the current understanding of the relationship between pyroptosis and liver diseases as well as the advances in TCM interventions to provide a resource for the identification of potential targets for TCM in the treatment of liver diseases.
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Affiliation(s)
- Wenxing He
- Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Canli Xu
- Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Dewen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yang Zheng
- Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Na Wang
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Minggang Wang
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Nan Mao
- Department of Acupuncture-Moxibustion and Tuina, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Ting Wang
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yanjie Li
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Patil D, Bhatt LK. Novel Therapeutic Avenues for Hypertrophic Cardiomyopathy. Am J Cardiovasc Drugs 2023; 23:623-640. [PMID: 37670168 DOI: 10.1007/s40256-023-00609-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/14/2023] [Indexed: 09/07/2023]
Abstract
Hypertrophic cardiomyopathy (HCM) is a complicated, heterogeneous genetic condition that causes left ventricular hypertrophy, fibrosis, hypercontractility, and decreased compliance. Despite the advances made over the past 3 decades in understanding the molecular and cellular mechanisms aggravating HCM, the relationship between pathophysiological stress stimuli and distinctive myocyte growth profiles is still imprecise. Currently, mavacamten, a selective and reversible inhibitor of cardiac myosin ATPase, is the only drug approved by the US FDA for the treatment of HCM. Thus, there is an unmet need for developing novel disease-specific therapeutic approaches. This article provides an overview of emerging therapeutic targets for the treatment of HCM based on various molecular pathways and novel developments that are hopefully soon to enter the clinical study. These newly discovered targets include the dual specificity tyrosine-phosphorylation-regulated kinase 1B, the absence of the melanoma 1 inflammasome, the leucine-rich repeat kinase 2 enzyme, and the cluster of differentiation 147.
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Affiliation(s)
- Dipti Patil
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (West), Mumbai, 400056, India
| | - Lokesh Kumar Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (West), Mumbai, 400056, India.
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Lu S, Li Y, Qian Z, Zhao T, Feng Z, Weng X, Yu L. Role of the inflammasome in insulin resistance and type 2 diabetes mellitus. Front Immunol 2023; 14:1052756. [PMID: 36993972 PMCID: PMC10040598 DOI: 10.3389/fimmu.2023.1052756] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023] Open
Abstract
The inflammasome is a protein complex composed of a variety of proteins in cells and which participates in the innate immune response of the body. It can be activated by upstream signal regulation and plays an important role in pyroptosis, apoptosis, inflammation, tumor regulation, etc. In recent years, the number of metabolic syndrome patients with insulin resistance (IR) has increased year by year, and the inflammasome is closely related to the occurrence and development of metabolic diseases. The inflammasome can directly or indirectly affect conduction of the insulin signaling pathway, involvement the occurrence of IR and type 2 diabetes mellitus (T2DM). Moreover, various therapeutic agents also work through the inflammasome to treat with diabetes. This review focuses on the role of inflammasome on IR and T2DM, pointing out the association and utility value. Briefly, we have discussed the main inflammasomes, including NLRP1, NLRP3, NLRC4, NLRP6 and AIM2, as well as their structure, activation and regulation in IR were described in detail. Finally, we discussed the current therapeutic options-associated with inflammasome for the treatment of T2DM. Specially, the NLRP3-related therapeutic agents and options are widely developed. In summary, this article reviews the role of and research progress on the inflammasome in IR and T2DM.
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Affiliation(s)
- Shen Lu
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Yanrong Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
| | - Zhaojun Qian
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Tiesuo Zhao
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
| | - Xiaogang Weng
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
- *Correspondence: Lili Yu, ; Xiaogang Weng,
| | - Lili Yu
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China
- *Correspondence: Lili Yu, ; Xiaogang Weng,
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11
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The Mechanisms of Systemic Inflammatory and Immunosuppressive Acute-on-Chronic Liver Failure and Application Prospect of Single-Cell Sequencing. J Immunol Res 2022; 2022:5091275. [PMID: 36387424 PMCID: PMC9646330 DOI: 10.1155/2022/5091275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 09/14/2022] [Accepted: 10/11/2022] [Indexed: 01/24/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a complex clinical syndrome, and patients often have high short-term mortality. It occurs with intense systemic inflammation, often accompanied by a proinflammatory event (such as infection or alcoholic hepatitis), and is closely related to single or multiple organ failure. Liver inflammation begins when innate immune cells (such as Kupffer cells (KCs)) are activated by binding of pathogen-associated molecular patterns (PAMPs) from pathogenic microorganisms or damage-associated molecular patterns (DAMPs) of host origin to their pattern recognition receptors (PRRs). Activated KCs can secrete inflammatory factors as well as chemokines and recruit bone marrow-derived cells such as neutrophils and monocytes to the liver to enhance the inflammatory process. Bacterial translocation may contribute to ACLF when there are no obvious precipitating events. Immunometabolism plays an important role in the process (including mitochondrial dysfunction, amino acid metabolism, and lipid metabolism). The late stage of ACLF is mainly characterized by immunosuppression. In this process, the dysfunction of monocyte and macrophage is reflected in the downregulation of HLA-DR and upregulation of MER tyrosine kinase (MERTK), which weakens the antigen presentation function and reduces the secretion of inflammatory cytokines. We also describe the specific function of bacterial translocation and the gut-liver axis in the process of ACLF. Finally, we also describe the transcriptomics in HBV-ACLF and the recent progress of single-cell RNA sequencing as well as its potential application in the study of ACLF in the future, in order to gain a deeper understanding of ACLF in terms of single-cell gene expression.
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12
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Yang J, Liu W. The Role of AIM2 Inflammasome in Knee Osteoarthritis. J Inflamm Res 2022; 15:6453-6461. [PMID: 36467990 PMCID: PMC9717587 DOI: 10.2147/jir.s392652] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Knee osteoarthritis (KOA), whose prevalence keeps rising, is still unsolved pathobiological/therapeutical problem. Historically, knee osteoarthritis was thought to be a "wear and tear" disease, while recent etiology hypotheses stressed it as a chronic, low-grade inflammatory disease. Inflammasomes mediated by the innate immunity systems have an important role in inflammatory diseases including KOA. A deluge of recent studies focused on the NLRP3 inflammasome with suggestions that its pharmacologic block would hinder degeneration. However, known inflammasomes are numerous and can also trigger IL-1β/IL-18 production and cells' pyroptotic death. Among them, AIM2 inflammasome is involved in key aspects of various acute and chronic inflammatory diseases. Therefore, while presently leaving out little-studied inflammasomes in KOA, this review focuses on the AIM2 inflammasomes that participate in KOA's complex mechanisms in conjunction with the activation of AIM2 inflammasomes in other diseases combined with the current studies on KOA mechanisms. Although human-specific data about it are relatively scant, we stress that only a holistic view including several inflammasomes including AIM2 inflammasome and other potential pathogenetic drivers will lead to successful therapy for knee osteoarthritis.
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Affiliation(s)
- Jiyong Yang
- The Fifth Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510095, People’s Republic of China
| | - Wengang Liu
- Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou, 510095, People’s Republic of China
- Correspondence: Wengang Liu, Orthopedics Department, Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou, 510095, People’s Republic of China, Email
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13
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Gan C, Cai Q, Tang C, Gao J. Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis. Front Immunol 2022; 13:896473. [PMID: 35707547 PMCID: PMC9189314 DOI: 10.3389/fimmu.2022.896473] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/04/2022] [Indexed: 01/18/2023] Open
Abstract
Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death. There are two main canonical and non-canonical signaling pathways that trigger inflammasome activation. Inflammasomes are expressed and assembled in parenchymal and nonparenchymal cells in response to liver injury in the liver. Additionally, the hepatocytes, biliary epithelial cells (cholangiocytes), hepatic stellate cells (HSCs), hepatic macrophages, and liver sinusoidal endothelial cells (LSECs) contribute to liver fibrosis via different mechanisms. However, the underlying mechanism of the inflammasome and pyroptosis in these liver cells in liver fibrosis remains elusive. This review summarizes the activation and function of inflammasome complexes and then discusses the association between inflammasomes, pyroptosis, and liver fibrosis. Unlike other similar reviewers, we will focus on the effect of inflammasome activation and pyroptosis in the various liver cells during the development of liver fibrosis. We will also highlight the latest progress of pharmacological intervention in inflammasome-mediated liver fibrosis.
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Affiliation(s)
- Can Gan
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiuyu Cai
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Jinhang Gao, ; ; Chengwei Tang,
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Jinhang Gao, ; ; Chengwei Tang,
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14
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Lillo S, Saleh M. Inflammasomes in Cancer Progression and Anti-Tumor Immunity. Front Cell Dev Biol 2022; 10:839041. [PMID: 35517498 PMCID: PMC9065266 DOI: 10.3389/fcell.2022.839041] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 01/28/2022] [Indexed: 12/16/2022] Open
Abstract
The inflammasomes are critical regulators of innate immunity, inflammation and cell death and have emerged as important regulators of cancer development and control. Inflammasomes are assembled by pattern recognition receptors (PRR) following the sensing of microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit inflammation through the oligomerization and activation of inflammatory caspases. These cysteinyl-aspartate proteases cleave the proinflammatory cytokines IL-1β and IL-18 into their biologically active mature form. The roles of the inflammasomes and associated pro-inflammatory cytokines vary greatly depending on the cancer type. Here we discuss recent studies highlighting contrasting roles of the inflammasome pathway in curbing versus promoting tumorigenesis. On one hand, the inflammasomes participate in stimulating anti-tumor immunity, but they have also been shown to contribute to immunosuppression or to directly promote tumor cell survival, proliferation, and metastasis. A better understanding of inflammasome functions in different cancers is thus critical for the design of novel cancer immunotherapies.
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Affiliation(s)
- Sebastian Lillo
- CNRS, ImmunoConcEpT, UMR 5164, University of Bordeaux, Bordeaux, France
| | - Maya Saleh
- CNRS, ImmunoConcEpT, UMR 5164, University of Bordeaux, Bordeaux, France
- >
Adjunct Professor, Department of Medicine, McGill University, Montreal, QC, Canada
- *Correspondence: Maya Saleh,
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15
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Albillos A, Martin-Mateos R, Van der Merwe S, Wiest R, Jalan R, Álvarez-Mon M. Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol 2022; 19:112-134. [PMID: 34703031 DOI: 10.1038/s41575-021-00520-7] [Citation(s) in RCA: 202] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 02/08/2023]
Abstract
The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease. Systemic inflammation and immune deficiency are the key components of CAID. Their severity is highly dynamic and progressive, paralleling cirrhosis stage. CAID involves two different immune phenotypes: the low-grade systemic inflammatory phenotype and the high-grade systemic inflammatory phenotype. The low-grade systemic inflammatory phenotype can be found in patients with compensated disease or clinical decompensation with no organ failure. In this phenotype, there is an exaggerated immune activation but the effector response is not markedly compromised. The high-grade systemic inflammatory phenotype is present in patients with acute-on-chronic liver failure, a clinical situation characterized by decompensation, organ failure and high short-term mortality. Along with high-grade inflammation, this CAID phenotype includes intense immune paralysis that critically increases the risk of infections and worsens prognosis. The intensity of CAID has important consequences on cirrhosis progression and correlates with the severity of liver insufficiency, bacterial translocation and organ failure. Therapies targeting the modulation of the dysfunctional immune response are currently being evaluated in preclinical and clinical studies.
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Affiliation(s)
- Agustín Albillos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. .,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.
| | - Rosa Martin-Mateos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Schalk Van der Merwe
- Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, University Inselspital, Bern, Switzerland
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Melchor Álvarez-Mon
- Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Department of Internal Medicine, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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16
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Abstract
The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on (a) signals and mechanisms of inflammasome activation, (b) the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and (c) potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation.
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Affiliation(s)
- Marcelle de Carvalho Ribeiro
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA; ,
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA; ,
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17
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Song Z, Gong Q, Guo J. Pyroptosis: Mechanisms and Links with Fibrosis. Cells 2021; 10:cells10123509. [PMID: 34944017 PMCID: PMC8700428 DOI: 10.3390/cells10123509] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is responsible for approximately 45% of deaths in the industrialized world and has been a major global healthcare burden. Excessive fibrosis is the primary cause of organ failure. However, there are currently no approved drugs available for the prevention or treatment of fibrosis-related diseases. It has become evident that fibrosis is characterized by inflammation. In a large number of studies of various organs in mice and humans, pyroptosis has been found to play a significant role in fibrosis. Pyroptosis is a form of programmed cell death mediated by the N-terminal fragment of cysteinyl aspartate-specific proteinase (caspase)-1-cleaved gasdermin D (GSDMD, producing GSDMD-N) that gives rise to inflammation via the release of some proinflammatory cytokines, including IL-1β, IL-18 and HMGB1. These cytokines can initiate the activation of fibroblasts. Inflammasomes, an important factor upstream of GSDMD, can activate caspase-1 to trigger the maturation of IL-1β and IL-18. Moreover, the inhibition of inflammasomes, proinflammatory cytokines and GSDMD can prevent the progression of fibrosis. This review summarizes the growing evidence indicating that pyroptosis triggers fibrosis, and highlights potential novel targets for antifibrotic therapies.
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Affiliation(s)
- Zihao Song
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou 434023, China;
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou 434023, China;
- Correspondence: (Q.G.); (J.G.)
| | - Jiawei Guo
- Department of Pharmacology, School of Medicine, Yangtze University, Jingzhou 434023, China
- Correspondence: (Q.G.); (J.G.)
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18
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García-Peñarrubia P, Ruiz-Alcaraz AJ, Ruiz-Ballester M, Ramírez-Pávez TN, Martínez-Esparza M. Recent insights into the characteristics and role of peritoneal macrophages from ascites of cirrhotic patients. World J Gastroenterol 2021; 27:7014-7024. [PMID: 34887625 PMCID: PMC8613641 DOI: 10.3748/wjg.v27.i41.7014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/02/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
Macrophages are a diverse myeloid cell population involved in innate and adaptive immune responses, embryonic development, wound repair, and regulation of tissue homeostasis. These cells link the innate and adaptive immunities and are crucial in the development and sustainment of various inflammatory diseases. Macrophages are tissue-resident cells in steady-state conditions; however, they are also recruited from blood monocytes after local pathogen invasion or tissue injury. Peritoneal macrophages vary based on their cell complexity, phenotype, and functional capabilities. These cells regulate inflammation and control bacterial infections in the ascites of decompensated cirrhotic patients. Our recent work reported several phenotypic and functional characteristics of these cells under both healthy and pathological conditions. A direct association between cell size, CD14/CD16 expression, intracellular level of GATA-6, and expression of CD206 and HLA-DR activation/maturation markers, indicate that the large peritoneal macrophage CD14highCD16high subset constitutes the mature phenotype of human resident peritoneal macrophages during homeostasis. Moreover, elevated expression of CD14/CD16 is related to the phagocytic capacity. The novel large CD14highCD16high peritoneal subpopulation is increased in the ascites of cirrhotic patients and is highly sensitive to lipopolysaccharide (LPS)-induced activation, thereby exhibiting features of inflammatory priming. Thus, phosphorylation of ERK1/2, PKB/Akt, and c-Jun is remarkably increased in response to LPS in vitro, whereas that of p38 MAPK is reduced compared with the monocyte-derived macrophages from the blood of healthy controls. Furthermore, in vitro activated monocyte-derived macrophages from ascites of cirrhotic patients secreted significantly higher levels of IL-6, IL-10, and TNF-α and lower amounts of IL-1β and IL-12 than the corresponding cells from healthy donor’s blood. Based on these results, other authors have recently reported that the surface expression level of CD206 can be used to identify mature, resident, inflammatory peritoneal macrophages in patients with cirrhosis. Soluble CD206 is released from activated large peritoneal macrophages, and increased concentrations in patients with cirrhosis and spontaneous bacterial peritonitis (SBP) indicate reduced odds of survival for 90 d. Hence, the level of soluble CD206 in ascites might be used to identify patients with SBP at risk of death. In conclusion, peritoneal macrophages present in ascites of cirrhotic patients display multiple phenotypic modifications characterized by reduced ratio of cells expressing several membrane markers, together with an increase in the ratios of complex and intermediate subpopulations and a decrease in the classic-like subset. These modifications may lead to the identification of novel pharmaceutical targets for prevention and treatment of hepatic damage.
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Affiliation(s)
- Pilar García-Peñarrubia
- Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia 30100, Spain
| | - Antonio José Ruiz-Alcaraz
- Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia 30100, Spain
| | - Miriam Ruiz-Ballester
- Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia 30100, Spain
| | - Tamara Nadira Ramírez-Pávez
- Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia 30100, Spain
| | - María Martínez-Esparza
- Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia 30100, Spain
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19
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Singanayagam A, Triantafyllou E. Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting. Front Immunol 2021; 12:661182. [PMID: 33868313 PMCID: PMC8051585 DOI: 10.3389/fimmu.2021.661182] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury results in immune-driven progressive fibrosis, with risk of cirrhosis development and impact on morbidity and mortality. Persistent liver cell damage and death causes immune cell activation and inflammation. Patients with advanced cirrhosis additionally experience pathological bacterial translocation, exposure to microbial products and chronic engagement of the immune system. Bacterial infections have a high incidence in cirrhosis, with spontaneous bacterial peritonitis being the most common, while the subsequent systemic inflammation, organ failure and immune dysregulation increase the mortality risk. Tissue-resident and recruited macrophages play a central part in the development of inflammation and fibrosis progression. In the liver, adipose tissue, peritoneum and intestines, diverse macrophage populations exhibit great phenotypic and functional plasticity determined by their ontogeny, epigenetic programming and local microenvironment. These changes can, at different times, promote or ameliorate disease states and therefore represent potential targets for macrophage-directed therapies. In this review, we discuss the evidence for macrophage phenotypic and functional alterations in tissue compartments during the development and progression of chronic liver failure in different aetiologies and highlight the potential of macrophage modulation as a therapeutic strategy for liver disease.
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Affiliation(s)
- Arjuna Singanayagam
- Infection and Immunity Clinical Academic Group, St. George’s University Hospitals NHS Foundation Trust, London, United Kingdom
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
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20
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Casulleras M, Zhang IW, López-Vicario C, Clària J. Leukocytes, Systemic Inflammation and Immunopathology in Acute-on-Chronic Liver Failure. Cells 2020; 9:E2632. [PMID: 33302342 PMCID: PMC7762372 DOI: 10.3390/cells9122632] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/20/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure(s) and high short-term mortality. ACLF frequently occurs in close temporal relationship to a precipitating event, such as acute alcoholic, drug-induced or viral hepatitis or bacterial infection and, in cases without precipitating events, probably related to intestinal translocation of bacterial products. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. This hyperinflammatory state ultimately impairs the host defensive mechanisms of immune cells, rendering ACLF patients immunocompromised and more vulnerable to secondary infections, and therefore to higher organ dysfunction and mortality. In this review, we describe the prevailing characteristics of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on cells of the innate immune system (i.e., monocytes and neutrophils), their triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]), their effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) and the consequences on tissue immunopathology. In addition, this review includes a chapter discussing new emerging therapies based on the modulation of leukocyte function by the administration of pleiotropic proteins such as albumin, Toll-like receptor 4 antagonists, interleukin-22 or stem cell therapy. Finally, the importance of finding an appropriate intervention that reduces inflammation without inducing immunosuppression is highlighted as one of the main therapeutic challenges in cirrhosis.
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Affiliation(s)
- Mireia Casulleras
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain; (M.C.); (I.W.Z.)
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, 08021 Barcelona, Spain
| | - Ingrid W. Zhang
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain; (M.C.); (I.W.Z.)
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, 08021 Barcelona, Spain
| | - Cristina López-Vicario
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain; (M.C.); (I.W.Z.)
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, 08021 Barcelona, Spain
| | - Joan Clària
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain; (M.C.); (I.W.Z.)
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, 08021 Barcelona, Spain
- Department of Biomedical Sciences, School of Medicine and Health Sciences, Universitat de Barcelona, 08036 Barcelona, Spain
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21
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Wang Z, Wang Q, Jin J, Rong X, Wu T, Qiu H, Wu R. The diagnostic role of AIM2 in Kawasaki disease. Clin Exp Med 2020; 21:41-47. [PMID: 33079289 DOI: 10.1007/s10238-020-00669-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 10/03/2020] [Indexed: 10/23/2022]
Abstract
Kawasaki disease (KD), a systemic vasculitis in children, may bring serious complications. However, the etiology of KD remains unclear. AIM2, an intracellular receptor, plays a vital role during the infection caused by a variety of pathogens. However, its role in KD remains unclear. The principal aim of the present research is to concentrate on the relation between AIM2 and KD. We detected the levels of AIM2, IL-18 and IL-1β in all subjects by ELISA. The conventional inflammatory indices were detected in all subjects, such as WBC, HB, CRP and so on. The serum concentrations of AIM2, IL-18 and IL-1β were notably upregulated in the KD group compared to the febrile group and healthy group, respectively. And the three indicators in the KD patients were greatly reduced after interpreted with IVIG. Furthermore, the expressions of IL-18 and IL-1β were positively correlated with AIM2. Meanwhile, the cutoff value of serum AIM2 level for the diagnosis of KD was 541.90 ng/L with the specificity of 60% and sensitivity of 92.5%, compared to the febrile controls. And the area under curve (AUC) of AIM2 was 0.771. And no difference was observed in patients with CALs when compared with patients without CALs. The serum AIM2, IL-18 and IL-1β might play a critical role during the progress of KD. AIM2 can be considered as a candidate indicator for Kawasaki disease diagnosis.
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Affiliation(s)
- Zhenquan Wang
- Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiaoyu Wang
- Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jiahui Jin
- Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xing Rong
- Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Tingting Wu
- Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huixian Qiu
- Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rongzhou Wu
- Children's Heart Center, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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22
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Lozano-Ruiz B, González-Navajas JM. The Emerging Relevance of AIM2 in Liver Disease. Int J Mol Sci 2020; 21:ijms21186535. [PMID: 32906750 PMCID: PMC7555176 DOI: 10.3390/ijms21186535] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 01/18/2023] Open
Abstract
Absent in melanoma 2 (AIM2) is a cytosolic receptor that recognizes double-stranded DNA (dsDNA) and triggers the activation of the inflammasome cascade. Activation of the inflammasome results in the maturation of inflammatory cytokines, such as interleukin (IL)-1 β and IL-18, and a form of cell death known as pyroptosis. Owing to the conserved nature of its ligand, AIM2 is important during immune recognition of multiple pathogens. Additionally, AIM2 is also capable of recognizing host DNA during cellular damage or stress, thereby contributing to sterile inflammatory diseases. Inflammation, either in response to pathogens or due to sterile cellular damage, is at the center of the most prevalent and life-threatening liver diseases. Therefore, during the last 15 years, the study of inflammasome activation in the liver has emerged as a new research area in hepatology. Here, we discuss the known functions of AIM2 in the pathogenesis of different hepatic diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), hepatitis B, liver fibrosis, and hepatocellular carcinoma (HCC).
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Affiliation(s)
- Beatriz Lozano-Ruiz
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain;
- Department of Pharmacology, Paediatrics and Organic Chemistry, University Miguel Hernández (UMH), 03550 San Juan, Alicante, Spain
| | - José M. González-Navajas
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain;
- Department of Pharmacology, Paediatrics and Organic Chemistry, University Miguel Hernández (UMH), 03550 San Juan, Alicante, Spain
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, 28029 Madrid, Spain
- Institute of Research, Development and Innovation in Healthcare Biotechnology in Elche (IDiBE), University Miguel Hernández, 03202 Elche, Alicante, Spain
- Correspondence: ; Tel.: +34-(965)-913-928
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Sharma BR, Karki R, Kanneganti TD. Role of AIM2 inflammasome in inflammatory diseases, cancer and infection. Eur J Immunol 2019; 49:1998-2011. [PMID: 31372985 DOI: 10.1002/eji.201848070] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/22/2019] [Accepted: 07/31/2019] [Indexed: 12/23/2022]
Abstract
AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.
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Affiliation(s)
- Bhesh Raj Sharma
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rajendra Karki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
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24
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Lutz P, Jeffery HC, Jones N, Birtwistle J, Kramer B, Nattermann J, Spengler U, Strassburg CP, Adams DH, Oo YH. NK Cells in Ascites From Liver Disease Patients Display a Particular Phenotype and Take Part in Antibacterial Immune Response. Front Immunol 2019; 10:1838. [PMID: 31440239 PMCID: PMC6694841 DOI: 10.3389/fimmu.2019.01838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 07/22/2019] [Indexed: 12/21/2022] Open
Abstract
Background and Aims: Ascites and spontaneous bacterial peritonitis (SBP) are frequent complications of liver cirrhosis. In spite of the clinical impact, knowledge about ascites as an immune cell compartment in liver disease is limited. Therefore, we analyzed NK cells in blood, ascites, and liver. Methods: Mononuclear cells from blood, ascites, and liver explants of patients with advanced liver disease were extracted by density gradient centrifugation. Phenotyping and analysis of functional responses were carried out using flow cytometry. Migratory potential was investigated with transwell chamber assays. NK cell metabolism was assessed by Seahorse technology. Results: NK cell frequency was increased in uninfected ascites compared to blood, but not to liver. Ascites NK cells were predominantly CD16positive. CD56bright ascites NK cells did not share the typical phenotype of their liver counterparts. In contrast to the inhibitory receptor NKG2A, expression of the activating receptor NKG2D was decreased on ascites and liver CD16positive NK cells. Ascites NK cells expressed higher levels of CXCR3 than blood or liver NK cells, corresponding to increased ascites levels of CXCL10. Blood NK cells migrated toward ascites. Stimulation of mononuclear cells with Escherichia coli led to downregulation of NKG2D expression and IL-12 and IL-18 mediated secretion of interferon-γ by ascites and liver, but not blood NK cells. In-vivo, ascites NK cells expressed higher levels of the activation marker CD69 and lower levels of NKG2D during SBP compared to uninfected ascites. Conclusion: Ascites NK cells display a particular phenotype and are implicated in local immune defense against translocating bacteria.
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Affiliation(s)
- Philipp Lutz
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research, University of Bonn, Bonn, Germany
| | - Hannah C. Jeffery
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Nicholas Jones
- Swansea University Medical School, Institute of Life Science, Swansea University, Swansea, United Kingdom
| | - Jane Birtwistle
- Human Biomaterial Resource Centre, University of Birmingham, Birmingham, United Kingdom
| | - Benjamin Kramer
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research, University of Bonn, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research, University of Bonn, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research, University of Bonn, Bonn, Germany
| | - Christian P. Strassburg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research, University of Bonn, Bonn, Germany
| | - David H. Adams
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Ye H. Oo
- National Institute of Health Research Liver Biomedical Research Unit Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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25
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Irvine KM, Ratnasekera I, Powell EE, Hume DA. Causes and Consequences of Innate Immune Dysfunction in Cirrhosis. Front Immunol 2019; 10:293. [PMID: 30873165 PMCID: PMC6401613 DOI: 10.3389/fimmu.2019.00293] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 02/05/2019] [Indexed: 12/15/2022] Open
Abstract
Liver cirrhosis is an increasing health burden and public health concern. Regardless of etiology, patients with cirrhosis are at risk of a range of life-threatening complications, including the development of infections, which are associated with high morbidity and mortality and frequent hospital admissions. The term Cirrhosis-Associated Immune Dysfunction (CAID) refers to a dynamic spectrum of immunological perturbations that develop in patients with cirrhosis, which are intimately linked to the underlying liver disease, and negatively correlated with prognosis. At the two extremes of the CAID spectrum are systemic inflammation, which can exacerbate clinical manifestations of cirrhosis such as hemodynamic derangement and kidney injury; and immunodeficiency, which contributes to the high rate of infection in patients with decompensated cirrhosis. Innate immune cells, in particular monocytes/macrophages and neutrophils, are pivotal effector and target cells in CAID. This review focuses on the pathophysiological mechanisms leading to impaired innate immune function in cirrhosis. Knowledge of the phenotypic manifestation and pathophysiological mechanisms of cirrhosis associated immunosuppression may lead to immune targeted therapies to reduce susceptibility to infection in patients with cirrhosis, and better biomarkers for risk stratification, and assessment of efficacy of novel immunotherapies.
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Affiliation(s)
- Katharine Margaret Irvine
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Isanka Ratnasekera
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Elizabeth E. Powell
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - David Arthur Hume
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
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26
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Wortmann M, Xiao X, Wabnitz G, Samstag Y, Hakimi M, Böckler D, Dihlmann S. AIM2 levels and DNA-triggered inflammasome response are increased in peripheral leukocytes of patients with abdominal aortic aneurysm. Inflamm Res 2019; 68:337-345. [DOI: 10.1007/s00011-019-01212-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 12/03/2018] [Accepted: 01/01/2019] [Indexed: 02/08/2023] Open
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27
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Khan S, Godfrey V, Zaki MH. Cytosolic Nucleic Acid Sensors in Inflammatory and Autoimmune Disorders. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 344:215-253. [PMID: 30798989 DOI: 10.1016/bs.ircmb.2018.10.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Innate immunity employs germline-encoded pattern recognition receptors (PRRs) to sense microbial pattern molecules. Recognition of pathogen-associated molecular patterns (PAMPs) by various PPRs located on the cell membrane or in the cytosol leads to the activation of cell signaling pathways and production of inflammatory mediators. Nucleic acids including DNA, RNA, and their derivatives are potent PAMPs which can be recognized by multiple PRRs to induce inflammatory responses. While nucleic acid sensors can also sense endogenous nucleic acids, they are capable of discriminating self from non-self. However, defects in nucleic acid sensing PRRs or dysregulation of nucleic acid sensing signaling pathways may cause excessive activation of the immune system resulting in the development of inflammatory and autoimmune diseases. This review will discuss the major pathways for sensing intracellular nucleic acids and how defects in these nucleic acid sensing are associated with different kinds of autoimmune and inflammatory disorders.
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Affiliation(s)
- Shahanshah Khan
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, United States
| | - Victoria Godfrey
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, United States
| | - Md Hasan Zaki
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, United States.
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28
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Martínez-Cardona C, Lozano-Ruiz B, Bachiller V, Peiró G, Algaba-Chueca F, Gómez-Hurtado I, Such J, Zapater P, Francés R, González-Navajas JM. AIM2 deficiency reduces the development of hepatocellular carcinoma in mice. Int J Cancer 2018; 143:2997-3007. [PMID: 30133699 DOI: 10.1002/ijc.31827] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 07/10/2018] [Accepted: 08/13/2018] [Indexed: 12/26/2022]
Abstract
Chronic liver inflammation is crucial in the pathogenesis of hepatocellular carcinoma (HCC). Activation of the inflammasome complex is a key inflammatory process that has been associated with different liver diseases, but its role in HCC development remains largely unexplored. Here we analyzed the impact of different inflammasome components, including absent in melanoma 2 (AIM2) and NOD-like receptor family pyrin domain containing 3 (NLRP3), in the development of diethylnitrosamine (DEN)-induced HCC in mice. Genetic inactivation of AIM2, but not NLRP3, reduces liver damage and HCC development in this model. AIM2 deficiency ameliorates inflammasome activation, liver inflammation and proliferative responses during HCC initiation. We also identified that AIM2 is highly expressed in Kupffer cells, and that AIM2-mediated production of IL-1β by these cells is enhanced after DEN-induced liver damage. Our data indicate that AIM2 promotes inflammation during carcinogenic liver injury and that it contributes to genotoxic HCC development in mice, thereby recognizing AIM2 as a potential therapeutic target in this disease.
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Affiliation(s)
- Claudia Martínez-Cardona
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Department of Pharmacology, University Miguel Hernández, Elche, Spain
| | - Beatriz Lozano-Ruiz
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Victoria Bachiller
- Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Gloria Peiró
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Pathology Department, Hospital General Universitario de Alicante, Alicante, Spain
| | - Francisco Algaba-Chueca
- Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Gómez-Hurtado
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - José Such
- Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Pedro Zapater
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Department of Pharmacology, University Miguel Hernández, Elche, Spain
| | - Rubén Francés
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Department of Clinical Medicine, University Miguel Hernández, Elche, Spain
| | - José Manuel González-Navajas
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,The Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Sino-French Hoffman Institute, Guangzhou Medical University, Guangzhou, China
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29
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Luan J, Ju D. Inflammasome: A Double-Edged Sword in Liver Diseases. Front Immunol 2018; 9:2201. [PMID: 30319645 PMCID: PMC6167446 DOI: 10.3389/fimmu.2018.02201] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 09/05/2018] [Indexed: 12/20/2022] Open
Abstract
Inflammasomes have emerged as critical innate sensors of host immune that defense against pathogen infection, metabolism syndrome, cellular stress and cancer metastasis in the liver. The assembly of inflammasome activates caspase-1, which promotes the maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), and initiates pyroptotic cell death (pyroptosis). IL-18 exerts pleiotropic effects on hepatic NK cells, priming FasL-mediated cytotoxicity, and interferon-γ (IFN-γ)-dependent responses to prevent the development of liver diseases. However, considerable attention has been attracted to the pathogenic role of inflammasomes in various acute and chronic liver diseases, including viral hepatitis, nanoparticle-induced liver injury, alcoholic and non-alcoholic steatohepatitis. In this review, we summarize the latest advances on the physiological and pathological roles of inflammasomes for further development of inflammasome-based therapeutic strategies for human liver diseases.
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Affiliation(s)
- Jingyun Luan
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Dianwen Ju
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
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30
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Algaba-Chueca F, de-Madaria E, Lozano-Ruiz B, Martínez-Cardona C, Quesada-Vázquez N, Bachiller V, Tarín F, Such J, Francés R, Zapater P, González-Navajas JM. The expression and activation of the AIM2 inflammasome correlates with inflammation and disease severity in patients with acute pancreatitis. Pancreatology 2017; 17:364-371. [PMID: 28342645 DOI: 10.1016/j.pan.2017.03.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 03/14/2017] [Accepted: 03/16/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute pancreatitis is an inflammatory disorder of the pancreas that is responsible for significant morbidity and mortality. The inflammasome pathway has acquired significant relevance in the pathogenesis of many inflammatory disorders, but its role in patients with acute pancreatitis still awaits clarification. METHODS We performed a prospective study in which 27 patients with acute pancreatitis and 16 healthy controls were included. We isolated peripheral blood mononuclear cells (PBMCs) and we assessed the expression and activation of different inflammasomes as well as their association with the clinical course of the disease. RESULTS Our results show that PBMCs from patients with acute pancreatitis have elevated expression of several components of the inflammasome complex, including the inflammasome-forming receptor absent in melanoma 2 (AIM2), early during the onset of the disease. Activation of the AIM2 or NLRP3 inflammasomes in PBMCs from patients with acute pancreatitis results in exacerbated IL-1β and IL-18 production compared with PBMCs from healthy controls. Furthermore, both AIM2 mRNA expression and AIM2-mediated production of IL-1β by PBMCs correlated with increased systemic inflammation in these patients. Last, AIM2 expression was further increased in those patients that developed transient or persistent organ failure (moderate or severe acute pancreatitis). CONCLUSIONS Our data demonstrates that AIM2 inflammasome expression and activation is increased early during the course of acute pancreatitis, and suggests that AIM2 activation may affect systemic inflammation and organ failure in these patients.
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Affiliation(s)
- Francisco Algaba-Chueca
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain
| | - Enrique de-Madaria
- Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain; Department of Gastroenterology, General Hospital of Alicante, Alicante, Spain
| | - Beatriz Lozano-Ruiz
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain; Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain
| | - Claudia Martínez-Cardona
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain; Department of Pharmacology, University Miguel Hernández, Alicante, Spain
| | - Noé Quesada-Vázquez
- Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain; Department of Gastroenterology, General Hospital of Alicante, Alicante, Spain
| | - Victoria Bachiller
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain
| | - Fabián Tarín
- Hematology Service, General Hospital of Alicante, Alicante, Spain
| | - José Such
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain; Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Rubén Francés
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain; Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain; Department of Clinical Medicine, University Miguel Hernández, Alicante, Spain
| | - Pedro Zapater
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain; Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain; Department of Pharmacology, University Miguel Hernández, Alicante, Spain
| | - José M González-Navajas
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain; Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain.
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31
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Magdaleno F, Blajszczak CC, Nieto N. Key Events Participating in the Pathogenesis of Alcoholic Liver Disease. Biomolecules 2017; 7:biom7010009. [PMID: 28134813 PMCID: PMC5372721 DOI: 10.3390/biom7010009] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 01/20/2017] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currently only partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aims to introduce the reader to the concept of alcohol-mediated liver damage and the mechanisms driving injury.
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Affiliation(s)
- Fernando Magdaleno
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
| | - Chuck C Blajszczak
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
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32
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de Jong PR, González-Navajas JM, Jansen NJG. The digestive tract as the origin of systemic inflammation. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2016; 20:279. [PMID: 27751165 PMCID: PMC5067918 DOI: 10.1186/s13054-016-1458-3] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Failure of gut homeostasis is an important factor in the pathogenesis and progression of systemic inflammation, which can culminate in multiple organ failure and fatality. Pathogenic events in critically ill patients include mesenteric hypoperfusion, dysregulation of gut motility, and failure of the gut barrier with resultant translocation of luminal substrates. This is followed by the exacerbation of local and systemic immune responses. All these events can contribute to pathogenic crosstalk between the gut, circulating cells, and other organs like the liver, pancreas, and lungs. Here we review recent insights into the identity of the cellular and biochemical players from the gut that have key roles in the pathogenic turn of events in these organ systems that derange the systemic inflammatory homeostasis. In particular, we discuss the dangers from within the gastrointestinal tract, including metabolic products from the liver (bile acids), digestive enzymes produced by the pancreas, and inflammatory components of the mesenteric lymph.
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Affiliation(s)
- Petrus R de Jong
- Department of Pediatric Intensive Care, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. .,Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
| | - José M González-Navajas
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Hospital General Universitario de Alicante, Alicante, Spain.,Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain
| | - Nicolaas J G Jansen
- Department of Pediatric Intensive Care, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
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33
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Gatselis NK, Skendros P, Ritis K, Dalekos GN. Severe liver involvement in two patients with long-term history of fever: remember familial Mediterranean fever. BMJ Case Rep 2016; 2016:bcr-2016-216941. [PMID: 27659912 DOI: 10.1136/bcr-2016-216941] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Familial Mediterranean fever (FMF) is characterised by recurrent, self-limited fever attacks and serositis. Severe liver involvement has rarely been reported. We present two FMF cases of a 55-year-old man and a 20-year-old woman in whom the prevailing manifestations were recurrent unexplained episodes of anicteric hepatitis (man) and recurrent severe jaundice (woman). A long-term history of recurrent self-limited episodes of fever was also claimed in both. After exclusion of infectious, malignant, autoimmune, and liver and biliary diseases, a diagnosis of FMF as confirmed by molecular analysis was established. The patients started colchicine 1 mg/day with immediate resolution of symptoms. During follow-up, no new episodes of fever and exacerbation of liver biochemical parameters have been recorded for 5 and 1 years. Physicians must keep FMF in mind in patients with recurrent episodes of unexplained severe liver impairment and fever and especially in regions like Mediterranean basin where hereditary periodic fever syndromes are common.
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Affiliation(s)
- Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Panagiotis Skendros
- First Department of Internal Medicine and Laboratory of Molecular Hematology, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos Ritis
- First Department of Internal Medicine and Laboratory of Molecular Hematology, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece
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34
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Bruns T, Reuken PA, Stengel S, Gerber L, Appenrodt B, Schade JH, Lammert F, Zeuzem S, Stallmach A. The prognostic significance of bacterial DNA in patients with decompensated cirrhosis and suspected infection. Liver Int 2016; 36:1133-42. [PMID: 26901072 DOI: 10.1111/liv.13095] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 02/11/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Circulating and peritoneal fragments of microbial DNA (bactDNA) are evidence for bacterial translocation in decompensated cirrhosis and may serve as a rational approach for antibiotic therapy when infection is suspected. METHODS Prospective multicenter study to investigate whether identification of bactDNA from blood or ascitic fluid (AF) by multiplex polymerase chain reaction (PCR) is associated with increased 90-day mortality in 218 patients with cirrhosis and signs of infection. RESULTS BactDNA in either compartment was detected in 134 (61%) patients, comprising 54 with bactDNA in blood and AF, 48 with AF bactDNA only, and 32 with blood bactDNA only. BactDNA was associated with spontaneous bacterial peritonitis and blood stream infections (SBP/BSI), acute-on-chronic liver failure (ACLF), encephalopathy and markers of inflammation. The prevalence of bactDNA in patients with proven SBP/BSI (36/49; 73%) was similar to that in patients with sterile ACLF (37/52; 71%). Actuarial 90-day survival was 56 ± 5% in the absence of bactDNA in both compartments and did not differ if bactDNA was detected in blood only (63 ± 9%), AF only (63 ± 7%), or in blood and AF (52 ± 7%). Predictors of 90-day mortality were SBP (HR = 3.10; 95% CI: 1.90-5.06), BSI (HR = 4.94; 95% CI: 2.71-9.02), and ACLF (HR = 2.20; 95% CI: 1.44-3.35). The detection of resistance genes in blood or AF in the absence of SBP/BSI (n = 11) was associated with poor 1-year survival (HR = 2.35; 95% CI: 1.03-5.35). CONCLUSIONS BactDNA in sterile body fluids did not indicate increased mortality in cirrhotic patients with suspected infection. Using multiplex PCR for risk stratification cannot be recommended in these patients.
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Affiliation(s)
- Tony Bruns
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Philipp A Reuken
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Sven Stengel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Ludmila Gerber
- Department of Internal Medicine I, Frankfurt University Hospital, Frankfurt, Germany
| | - Beate Appenrodt
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany
| | - Johannes H Schade
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Frank Lammert
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, Frankfurt University Hospital, Frankfurt, Germany
| | - Andreas Stallmach
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
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González-Navajas JM. Inflammasome activation in decompensated liver cirrhosis. World J Hepatol 2016; 8:207-210. [PMID: 26855691 PMCID: PMC4733463 DOI: 10.4254/wjh.v8.i4.207] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 06/10/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023] Open
Abstract
Inflammation participates in the pathogenesis of many liver diseases, including liver cirrhosis. Certain inflammatory citokines, such as interleukin (IL)-1β and IL-18, are produced after the activation of a multiprotein complex known as the inflammasome. Activation of the inflammasome has been documented in several liver diseases, but its role in the development and progression of liver cirrhosis or the complications associated with this disease is still largely unknown. We have recently studied the impact of the inflammasome in the sterile inflammatory response that takes place in the ascitic fluid of patients with decompensated cirrhosis, providing evidence that activation of the absent in melanoma 2 (AIM2) inflammasome is an important response in these patients. Ascitic fluid-derived macrophages were able to mount a very robust AIM2-mediated response even in the absence of a priming signal, which is usually required for the full activation of all the inflammasomes. In addition, high level of inflammasome activation in these patients was associated with a higher degree of liver disease and an increased incidence of spontaneous bacterial peritonitis. These results may help explain the exacerbated inflammatory response that usually occurs in patients with decompensated cirrhosis in the absence of detectable infections. Thus, inflammasomes should be considered as possible therapeutic targets in sterile inflammatory complications in patients with cirrhosis.
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Man SM, Karki R, Kanneganti TD. AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity. Eur J Immunol 2015; 46:269-80. [PMID: 26626159 DOI: 10.1002/eji.201545839] [Citation(s) in RCA: 252] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 11/13/2015] [Accepted: 11/26/2015] [Indexed: 12/15/2022]
Abstract
Recognition of DNA by the cell is an important immunological signature that marks the initiation of an innate immune response. AIM2 is a cytoplasmic sensor that recognizes dsDNA of microbial or host origin. Upon binding to DNA, AIM2 assembles a multiprotein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the proinflammatory cytokines pro-IL-1β and pro-IL-18. Release of microbial DNA into the cytoplasm during infection by Francisella, Listeria, Mycobacterium, mouse cytomegalovirus, vaccinia virus, Aspergillus, and Plasmodium species leads to activation of the AIM2 inflammasome. In contrast, inappropriate recognition of cytoplasmic self-DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis, and other autoimmune and inflammatory diseases. Inflammasome-independent functions of AIM2 have also been described, including the regulation of the intestinal stem cell proliferation and the gut microbiota ecology in the control of colorectal cancer. In this review we provide an overview of the latest research on AIM2 inflammasome and its role in infection, cancer, and autoimmunity.
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Affiliation(s)
- Si Ming Man
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rajendra Karki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
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Martínez-Esparza M, Tristán-Manzano M, Ruiz-Alcaraz AJ, García-Peñarrubia P. Inflammatory status in human hepatic cirrhosis. World J Gastroenterol 2015; 21:11522-11541. [PMID: 26556984 PMCID: PMC4631958 DOI: 10.3748/wjg.v21.i41.11522] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 07/31/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.
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Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63:1272-84. [PMID: 26192220 DOI: 10.1016/j.jhep.2015.07.004] [Citation(s) in RCA: 430] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 07/06/2015] [Accepted: 07/07/2015] [Indexed: 02/06/2023]
Abstract
The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance.
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Affiliation(s)
- Mauro Bernardi
- Department of Medical and Surgical Sciences - Alma Mater Studiorum, University of Bologna, Italy; Semeiotica Medica, Policlinico S. Orsola-Malpighi, Bologna, Italy.
| | - Richard Moreau
- Inserm, U(1149), Centre de Recherche sur l'Inflammation (CRI), Paris, France; UMR_S(1149), Université Paris Diderot, Faculté de Médecine, Paris, France; Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France
| | - Paolo Angeli
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, United States; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
| | - Vicente Arroyo
- Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques Agust Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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Abstract
Inflammation contributes to the pathogenesis of most acute and chronic liver diseases. Inflammasomes are multiprotein complexes that can sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which proteolytically activates the cytokines IL-1β and IL-18. In contrast to other inflammatory responses, inflammasome activation uniquely requires two signals to induce inflammation, therefore setting an increased threshold. IL-1β, generated upon caspase-1 activation, provides positive feed-forward stimulation for inflammatory cytokines, thereby amplifying inflammation. Inflammasome activation has been studied in different human and experimental liver diseases and has been identified as a major contributor to hepatocyte damage, immune cell activation and amplification of liver inflammation. In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression. Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia-reperfusion injury and paracetamol-induced liver injury. The application and translation of these discoveries into therapies promises novel approaches in the treatment of inflammation in liver disease.
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Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605, USA
| | - Jan Petrasek
- Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605, USA
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Gustot T. Absent in melanoma (AIM2) but present in ascitic fluid macrophages from patients with cirrhosis. J Hepatol 2015; 62:11-2. [PMID: 25308173 DOI: 10.1016/j.jhep.2014.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Revised: 09/29/2014] [Accepted: 10/01/2014] [Indexed: 12/04/2022]
Affiliation(s)
- Thierry Gustot
- Department of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
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Jiang XL, Feng Q, Li WH, Xu M, Kang JS, Wei LX. Complete sequence of a hepatic cirrhosis inbred C57BL/6 mice model mitochondrial genome. Mitochondrial DNA A DNA Mapp Seq Anal 2014; 27:1817-8. [PMID: 25269002 DOI: 10.3109/19401736.2014.963841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In the present work we undertook the complete mitochondrial genome sequencing of an important hepatic cirrhosis model inbred C57BL/6 strain for the first time. Its mitogenome was 16,312 bp and coding 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes. A total of 96 SNPs were examined when compared to reference BN sequence.
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Affiliation(s)
- Xiao-Ling Jiang
- a Department of Pathology , General Hospital of PLA , Beijing , P.R. China .,b Department of Pathology , The 88th Hospital of PLA, Tai'an , Shandong Province , P.R. China
| | - Qiao Feng
- c Department of General Surgery , The 88th Hospital of PLA, Tai'an , Shandong Province , P.R. China , and
| | - Wei-Hong Li
- d Department of Pathology and Pathophysiology , Taishan Medical College , Tai'an, Shandong Province , P.R. China
| | - Min Xu
- b Department of Pathology , The 88th Hospital of PLA, Tai'an , Shandong Province , P.R. China
| | - Jun-Sheng Kang
- c Department of General Surgery , The 88th Hospital of PLA, Tai'an , Shandong Province , P.R. China , and
| | - Li-Xin Wei
- a Department of Pathology , General Hospital of PLA , Beijing , P.R. China
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