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1
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Shin Y, Bae H, Lee C, Rhee I. The dynamic roles of macrophages extracellular traps (METs) in immune regulation. Arch Pharm Res 2025; 48:293-304. [PMID: 40186802 DOI: 10.1007/s12272-025-01540-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/27/2025] [Indexed: 04/07/2025]
Abstract
Macrophages are crucial to innate immunity, eliminating pathogens and damaged tissues through phagocytosis and modulating immune responses. Recently, macrophage extracellular traps (METs) have been identified as chromatin-based structures composed of DNA and various immune-related proteins. While METs play a defensive role in trapping and neutralizing pathogens, they are also implicated in disease pathology, contributing to chronic inflammation, tissue damage, and immune dysregulation. The precise mechanisms regulating MET formation are still under investigation, but emerging evidence indicates the involvement of various regulatory factors. Dysregulated MET activity has been associated with various diseases, including autoimmune disorders, cancer, and neurological conditions. A deeper understanding of MET mechanisms and their pathological impact may offer novel therapeutic strategies. Given the limited number of reviews and articles on METs, this review provides valuable insights into MET formation, regulatory pathways, and their role in disease progression.
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Affiliation(s)
- Yunjin Shin
- Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea
| | - Hanyoung Bae
- Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea
| | - Chaelin Lee
- Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea
| | - Inmoo Rhee
- Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea.
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2
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Rasquel-Oliveira FS, Ribeiro JM, Martelossi-Cebinelli G, Costa FB, Nakazato G, Casagrande R, Verri WA. Staphylococcus aureus in Inflammation and Pain: Update on Pathologic Mechanisms. Pathogens 2025; 14:185. [PMID: 40005560 PMCID: PMC11858194 DOI: 10.3390/pathogens14020185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 01/23/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Staphylococcus aureus (S. aureus) is a Gram-positive bacterium of significant clinical importance, known for its versatility and ability to cause a wide array of infections, such as osteoarticular, pulmonary, cardiovascular, device-related, and hospital-acquired infections. This review describes the most recent evidence of the pathogenic potential of S. aureus, which is commonly part of the human microbiota but can lead to severe infections. The prevalence of pathogenic S. aureus in hospital and community settings contributes to substantial morbidity and mortality, particularly in individuals with compromised immune systems. The immunopathogenesis of S. aureus infections involves intricate interactions with the host immune and non-immune cells, characterized by various virulence factors that facilitate adherence, invasion, and evasion of the host's defenses. This review highlights the complexity of S. aureus infections, ranging from mild to life-threatening conditions, and underscores the growing public health concern posed by multidrug-resistant strains, including methicillin-resistant S. aureus (MRSA). This article aims to provide an updated perspective on S. aureus-related infections, highlighting the main diseases linked to this pathogen, how the different cell types, virulence factors, and signaling molecules are involved in the immunopathogenesis, and the future perspectives to overcome the current challenges to treat the affected individuals.
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Affiliation(s)
- Fernanda S. Rasquel-Oliveira
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil; (F.S.R.-O.)
| | - Jhonatan Macedo Ribeiro
- Department of Microbiology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil (G.N.)
| | - Geovana Martelossi-Cebinelli
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil; (F.S.R.-O.)
| | - Fernanda Barbosa Costa
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil; (F.S.R.-O.)
| | - Gerson Nakazato
- Department of Microbiology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil (G.N.)
| | - Rubia Casagrande
- Department of Pharmaceutical Sciences, Center of Health Science, Londrina State University, Londrina 86038-440, PR, Brazil
| | - Waldiceu A. Verri
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Immunology, Parasitology and General Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, PR, Brazil; (F.S.R.-O.)
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Yu F, Chen J, Zhang X, Ma Z, Wang J, Wu Q. Role of Neutrophil Extracellular Traps in Hypertension and Their Impact on Target Organs. J Clin Hypertens (Greenwich) 2025; 27:e14942. [PMID: 39686847 PMCID: PMC11771816 DOI: 10.1111/jch.14942] [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: 06/13/2024] [Revised: 10/27/2024] [Accepted: 10/29/2024] [Indexed: 12/18/2024]
Abstract
Hypertension is the predominant cause of cardiovascular diseases (CVDs) globally, and essential hypertension (EH) represents a significant public health challenge due to its multifactorial etiology involving complex interactions between genetic and environmental factors. However, the pathogenesis of EH is still unclear. Hypertension is a dysregulation in the renin-angiotensin-aldosterone system and sympathetic nervous system, both regulating saline homeostasis and cardiovascular function. However, current therapeutic interventions targeting these systems have limited efficacy in approximately 40% of cases, suggesting the involvement of alternative mechanisms. Inflammation is associated with the occurrence and progression of hypertension, but the underlying mechanism remains elusive, while chronic inflammation leads to tissue damage, fibrosis, and irreversible organ dysfunction. The development and maintenance of EH are caused by endothelial dysfunction, oxidative stress, and chronic inflammation. Neutrophils are involved in both acute and chronic inflammation since they represent the primary line of defense against inflammatory insults once recruited to the inflamed site where they remove harmful impurities. The process involving the formation of neutrophil extracellular traps (NETs) is called NETosis are involved in the pathogenesis and progression of CVDs, including coronary artery disease, acute myocardial infarction, peripheral arterial disease, heart failure, and atrial fibrillation. Recent investigations demonstrated that NETs facilitate the development of hypertension; however, the precise role of NETs in hypertension remains largely elusive. Therefore, this review aims to provide an overview of the current understanding regarding the involvement of NETosis in hypertension and explore the potential therapies targeting NETs for future interventions.
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Affiliation(s)
- Fei Yu
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Jianshu Chen
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Xiaowei Zhang
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Zhengke Ma
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Jingtao Wang
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Qiang Wu
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
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4
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Cerdeira CD, Brigagão MRPL. Targeting Macrophage Polarization in Infectious Diseases: M1/M2 Functional Profiles, Immune Signaling and Microbial Virulence Factors. Immunol Invest 2024; 53:1030-1091. [PMID: 38913937 DOI: 10.1080/08820139.2024.2367682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
INTRODUCTION An event of increasing interest during host-pathogen interactions is the polarization of patrolling/naive monocytes (MOs) into macrophage subsets (MФs). Therapeutic strategies aimed at modulating this event are under investigation. METHODS This review focuses on the mechanisms of induction/development and profile of MФs polarized toward classically proinflammatory (M1) or alternatively anti-inflammatory (M2) phenotypes in response to bacteria, fungi, parasites, and viruses. RESULTS AND DISCUSSION It highlights nuclear, cytoplasmic, and cell surface receptors (pattern recognition receptors/PPRs), microenvironmental mediators, and immune signaling. MФs polarize into phenotypes: M1 MФs, activated by IFN-γ, pathogen-associated molecular patterns (PAMPs, e.g. lipopolysaccharide) and membrane-bound PPRs ligands (TLRs/CLRs ligands); or M2 MФs, induced by interleukins (ILs-4, -10 and -13), antigen-antibody complexes, and helminth PAMPs. Polarization toward M1 and M2 profiles evolve in a pathogen-specific manner, with or without canonicity, and can vary widely. Ultimately, this can result in varying degrees of host protection or more severe disease outcome. On the one hand, the host is driving effective MФs polarization (M1 or M2); but on the other hand, microorganisms may skew the polarization through virulence factors to increase pathogenicity. Cellular/genomic reprogramming also ensures plasticity of M1/M2 phenotypes. Because modulation of polarization can occur at multiple points, new insights and emerging perspectives may have clinical implications during the inflammation-to-resolution transition; translated into practical applications as for therapeutic/vaccine design target to boost microbicidal response (M1, e.g. triggering oxidative burst) with specifics PAMPs/IFN-γ or promote tissue repair (M2, increasing arginase activity) via immunotherapy.
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Alemie MN, Bright R, Nguyen NH, Truong VK, Palms D, Hayball JD, Vasilev K. Surface Chemistry Induced IgG Unfolding and Modulation of Immune Responses. ACS APPLIED MATERIALS & INTERFACES 2024; 16:50507-50523. [PMID: 39263871 DOI: 10.1021/acsami.4c12883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Immunoglobulin G (IgG) comprises a significant portion of the protein corona that forms on biomaterial surfaces and holds a pivotal role in modulating host immune responses. To shed light on the important relationship between biomaterial surface functionality, IgG adsorption, and innate immune responses, we prepared, using plasma deposition, four surface coatings with specific chemistries, wettability, and charge. We found that nitrogen-containing coatings such as these deposited from allylamine (AM) and 2-methyl-2-oxazoline (POX) cause the greatest IgG unfolding, while hydrophilic acrylic acid (AC) surfaces allowed for the retention of the protein structure. Structural changes in IgG significantly modulated macrophage attachment, migration, polarization, and the expression of pro- and anti-inflammatory cytokines. Unfolded IgG on the POX and AM surfaces enhanced macrophage attachment, migration, extracellular trap release, and pro-inflammatory factors production such as IL-6 and TNF-α. Retention of IgG structure on the AC surface downregulated inflammatory responses. The findings of this study demonstrate that the retention of protein structure is an essential factor that must be taken into consideration when designing biomaterial surfaces. Our study indicates that using hydrophilic surface coatings could be a promising strategy for designing immune-modulatory biomaterials for clinical applications.
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Affiliation(s)
- Markos Negash Alemie
- Experimental Therapeutics Laboratory, UniSA Clinical and Health Sciences. University of South Australia, City East Campus, Adelaide 5000, Australia
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
| | - Richard Bright
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
| | - Ngoc Huu Nguyen
- School of Biomedical Engineering, University of Sydney, Darlington, New South Wales 2006, Australia
| | - Vi Khanh Truong
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
| | - Dennis Palms
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
| | - John D Hayball
- Experimental Therapeutics Laboratory, UniSA Clinical and Health Sciences. University of South Australia, City East Campus, Adelaide 5000, Australia
| | - Krasimir Vasilev
- College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
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Dong T, Barasa L, Yu X, Ouyang W, Shao L, Quan C, Wang SH, Zhang J, Salmon M, Tsung A, Alam HB, Ma J, Thompson PR, Li Y. AFM41a: A Novel PAD2 Inhibitor for Sepsis Treatment-Efficacy and Mechanism. Int J Biol Sci 2024; 20:5043-5055. [PMID: 39430255 PMCID: PMC11488583 DOI: 10.7150/ijbs.97166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 09/05/2024] [Indexed: 10/22/2024] Open
Abstract
Pseudomonas aeruginosa (PA) infection can cause pneumonia and sepsis by activating peptidyl-arginine deiminase (PAD) and triggering the formation of neutrophil extracellular traps (NETs). Our previous research has elucidated the crucial role of PAD2 in regulating CitH3 production and NETosis signaling following bacterial infection. Therefore, targeting PAD2 with selective inhibitors holds promise for treating PA-induced sepsis. Here, we compare the structure and function of two PAD2 inhibitors, AFM32a and AFM41a, and investigate their biological effects in mice subjected with PA. We analyze their impact on PAD2 inhibition, macrophage polarization, and other host defense mechanisms against PA-induced sepsis utilizing both in vivo and in vitro approaches. Our findings demonstrate that both PAD2 inhibitors (AFM32a and AFM41a) and Pad2 deficiency substantially enhance protection against PA-induced sepsis, with AFM41a showing superior efficacy over AFM32a. This protective effect is marked by improved survival rates, reduced bacterial growth in mice subjected to PA infection, and the promotion of M2 macrophage polarization coupled with enhanced autophagic activity. Our results advocate for targeting PAD2 as an effective strategy to bolster host defenses against PA infection. Utilizing AFM41a to promote M2 macrophage polarization and autophagy offers promising avenues for the treatment of PA infection and the improvement of sepsis outcomes.
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Affiliation(s)
- Tao Dong
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
- Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Leonard Barasa
- Program in Chemical Biology, Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Xin Yu
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
- Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China
| | - Wenlu Ouyang
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Changsha, China
| | - Liujiazi Shao
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Chao Quan
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
- Department of Urology, The Xiangya Hospital, Changsha, China
| | - Su He Wang
- Internal Medicine, Division of Allergy, University of Michigan Health System, Ann Arbor, MI, USA
| | - Jifeng Zhang
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Morgan Salmon
- Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Allan Tsung
- Department of Surgery, Division of Surgical Science, University of Virginia, Charlottesville, VA 22903, USA
| | - Hasan B. Alam
- Department of Surgery, Northwestern University, Arkes Pavilion, 676 N St Clair St Ste 2320, Chicago, IL 60611, USA
| | - Jianjie Ma
- Department of Surgery, Division of Surgical Science, University of Virginia, Charlottesville, VA 22903, USA
| | - Paul R. Thompson
- Program in Chemical Biology, Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Yongqing Li
- Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA
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7
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Baz AA, Hao H, Lan S, Li Z, Liu S, Jin X, Chen S, Chu Y. Emerging insights into macrophage extracellular traps in bacterial infections. FASEB J 2024; 38:e23767. [PMID: 38924166 DOI: 10.1096/fj.202400739r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024]
Abstract
Macrophages possess a diverse range of well-defined capabilities and roles as phagocytes, encompassing the regulation of inflammation, facilitation of wound healing, maintenance of tissue homeostasis, and serving as a crucial element in the innate immune response against microbial pathogens. The emergence of extracellular traps is a novel strategy of defense that has been observed in several types of innate immune cells. In response to infection, macrophages are stimulated and produce macrophage extracellular traps (METs), which take the form of net-like structures, filled with strands of DNA and adorned with histones and other cellular proteins. METs not only capture and eliminate microorganisms but also play a role in the development of certain diseases such as inflammation and autoimmune disorders. The primary objective of this study is to examine the latest advancements in METs for tackling bacterial infections. We also delve into the current knowledge and tactics utilized by bacteria to elude or endure the effects of METs. Through this investigation, we hope to shed light on the intricate interactions between bacteria and the host's immune system, particularly in the context of microbicidal effector mechanisms of METs. The continued exploration of METs and their impact on host defense against various pathogens opens up new avenues for understanding and potentially manipulating the immune system's response to infections.
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Affiliation(s)
- Ahmed Adel Baz
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Assiut, Egypt
| | - Huafang Hao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Shimei Lan
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Zhangcheng Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Shuang Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Xiangrui Jin
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Shengli Chen
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Yuefeng Chu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
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8
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Hu W, Zhang X, Sheng H, Liu Z, Chen Y, Huang Y, He W, Luo G. The mutual regulation between γδ T cells and macrophages during wound healing. J Leukoc Biol 2024; 115:840-851. [PMID: 37493223 DOI: 10.1093/jleuko/qiad087] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 07/08/2023] [Accepted: 07/20/2023] [Indexed: 07/27/2023] Open
Abstract
Macrophages are the main cells shaping the local microenvironment during wound healing. As the prime T cells in the skin, γδ T cells participate in regulating microenvironment construction, determining their mutual regulation helps to understand the mechanisms of wound healing, and explore innovative therapeutic options for wound repair. This review introduced their respective role in wound healing firstly, and then summarized the regulatory effect of γδ T cells on macrophages, including chemotaxis, polarization, apoptosis, and pyroptosis. Last, the retrograde regulation on γδ T cells by macrophages was also discussed. The main purpose is to excavate novel interventions for treating wound and provide new thought for further research.
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Affiliation(s)
- Wengang Hu
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), ShaPingBa District, Chongqing 400038, China
- Chongqing Key Laboratory for Disease Proteomics, ShaPingBa District, Chongqing 400038, China
| | - Xiaorong Zhang
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), ShaPingBa District, Chongqing 400038, China
- Chongqing Key Laboratory for Disease Proteomics, ShaPingBa District, Chongqing 400038, China
| | - Hao Sheng
- Urology Department, Second Affiliated Hospital, Third Military Medical University (Army Medical University), XinQiao District, Chongqing 400037, China
| | - Zhongyang Liu
- Department of Plastic Surgery, First Affiliated Hospital, Zhengzhou University, ErQi District, Zhengzhou, Henan 450000, China
| | - Yunxia Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), ShaPingBa District, Chongqing 400038, China
- Chongqing Key Laboratory for Disease Proteomics, ShaPingBa District, Chongqing 400038, China
| | - Yong Huang
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), ShaPingBa District, Chongqing 400038, China
- Chongqing Key Laboratory for Disease Proteomics, ShaPingBa District, Chongqing 400038, China
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), ShaPingBa District, Chongqing 400038, China
- Chongqing Key Laboratory for Disease Proteomics, ShaPingBa District, Chongqing 400038, China
| | - Gaoxing Luo
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), ShaPingBa District, Chongqing 400038, China
- Chongqing Key Laboratory for Disease Proteomics, ShaPingBa District, Chongqing 400038, China
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9
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Vandepas LE, Stefani C, Domeier PP, Traylor-Knowles N, Goetz FW, Browne WE, Lacy-Hulbert A. Extracellular DNA traps in a ctenophore demonstrate immune cell behaviors in a non-bilaterian. Nat Commun 2024; 15:2990. [PMID: 38582801 PMCID: PMC10998917 DOI: 10.1038/s41467-024-46807-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 03/08/2024] [Indexed: 04/08/2024] Open
Abstract
The formation of extracellular DNA traps (ETosis) is a first response mechanism by specific immune cells following exposure to microbes. Initially characterized in vertebrate neutrophils, cells capable of ETosis have been discovered recently in diverse non-vertebrate taxa. To assess the conservation of ETosis between evolutionarily distant non-vertebrate phyla, we observed and quantified ETosis using the model ctenophore Mnemiopsis leidyi and the oyster Crassostrea gigas. Here we report that ctenophores - thought to have diverged very early from the metazoan stem lineage - possess immune-like cells capable of phagocytosis and ETosis. We demonstrate that both Mnemiopsis and Crassostrea immune cells undergo ETosis after exposure to diverse microbes and chemical agents that stimulate ion flux. We thus propose that ETosis is an evolutionarily conserved metazoan defense against pathogens.
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Affiliation(s)
- Lauren E Vandepas
- NRC Research Associateship Program, Seattle, WA, USA.
- Northwest Fisheries Science Center, National Oceanographic and Atmospheric Administration, Seattle, WA, 98112, USA.
- Benaroya Research Institute at Virginia Mason, Seattle, WA, 98101, USA.
- Department of Biology, University of Miami, Coral Gables, FL, 33146, USA.
| | - Caroline Stefani
- Benaroya Research Institute at Virginia Mason, Seattle, WA, 98101, USA
| | - Phillip P Domeier
- Benaroya Research Institute at Virginia Mason, Seattle, WA, 98101, USA
| | - Nikki Traylor-Knowles
- Rosenstiel School of Marine and Atmospheric Sciences, University of Miami, Miami, FL, 33149, USA
| | - Frederick W Goetz
- Northwest Fisheries Science Center, National Oceanographic and Atmospheric Administration, Seattle, WA, 98112, USA
| | - William E Browne
- Department of Biology, University of Miami, Coral Gables, FL, 33146, USA
| | - Adam Lacy-Hulbert
- Benaroya Research Institute at Virginia Mason, Seattle, WA, 98101, USA
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10
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Lawrence J, Barrow P, Foster N. Porcine Monocyte DNA Traps Formed during Infection with Pathogenic Clostridioides difficile Strains. Pathogens 2024; 13:228. [PMID: 38535571 PMCID: PMC10975479 DOI: 10.3390/pathogens13030228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/21/2024] [Accepted: 02/26/2024] [Indexed: 02/11/2025] Open
Abstract
Clostridioides (Clostridium) difficile is an enteric pathogen of several mammalian species including man, frequently involving nosocomial resurgence, following oral administration of broad-spectrum antibiotics, but also with human-to-human infection occurring, and neonatal pigs with zoonotic transmission. To date, the immune response to C. difficile has mostly focused on neutrophils and cytokine/chemokines, particularly in human infection. The neonatal pig is now recognized as a valuable model for human infection. We show that porcine monocytes respond to C. difficile differently compared with many other bacterial infections. Infection of porcine monocytes with human C. difficile strains CD630 (Ribotype 078) or R20291 (Ribotype 027) for 3 or 24 h post-infection (pi) resulted in a lack of oxidative burst or nitrite ion production when compared to uninfected controls (p > 0.05). The survival dynamics of both CD630 and R20291 in monocytes were similar with intracellular bacterial numbers being similar at 3 h pi and 24 h pi (p > 0.05). However, we show that porcine monocytes entrap C. difficile via extracellular DNA traps. This process began as early as 3 h pi, and at 24 h pi the nuclei appeared to be depleted of DNA, although extracellular DNA was associated with the cell membrane. Our preliminary study also suggests that entrapment of C. difficile by extracellular DNA may occur via a process of monocyte etosis.
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Affiliation(s)
- Jade Lawrence
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham LE12 5RD, UK;
| | - Paul Barrow
- School of Veterinary Medicine, University of Surrey, Daphne Jackson Road, Guildford GU2 7AL, UK;
| | - Neil Foster
- Department of Veterinary and Animal Science, SRUC Aberdeen, Craibstone Campus, Aberdeen AB21 9YA, UK
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11
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Sándor N, Schneider AE, Matola AT, Barbai VH, Bencze D, Hammad HH, Papp A, Kövesdi D, Uzonyi B, Józsi M. The human factor H protein family - an update. Front Immunol 2024; 15:1135490. [PMID: 38410512 PMCID: PMC10894998 DOI: 10.3389/fimmu.2024.1135490] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 01/08/2024] [Indexed: 02/28/2024] Open
Abstract
Complement is an ancient and complex network of the immune system and, as such, it plays vital physiological roles, but it is also involved in numerous pathological processes. The proper regulation of the complement system is important to allow its sufficient and targeted activity without deleterious side-effects. Factor H is a major complement regulator, and together with its splice variant factor H-like protein 1 and the five human factor H-related (FHR) proteins, they have been linked to various diseases. The role of factor H in inhibiting complement activation is well studied, but the function of the FHRs is less characterized. Current evidence supports the main role of the FHRs as enhancers of complement activation and opsonization, i.e., counter-balancing the inhibitory effect of factor H. FHRs emerge as soluble pattern recognition molecules and positive regulators of the complement system. In addition, factor H and some of the FHR proteins were shown to modulate the activity of immune cells, a non-canonical function outside the complement cascade. Recent efforts have intensified to study factor H and the FHRs and develop new tools for the distinction, quantification and functional characterization of members of this protein family. Here, we provide an update and overview on the versatile roles of factor H family proteins, what we know about their biological functions in healthy conditions and in diseases.
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Affiliation(s)
- Noémi Sándor
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, Budapest, Hungary
| | | | | | - Veronika H. Barbai
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Dániel Bencze
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Hani Hashim Hammad
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Alexandra Papp
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Dorottya Kövesdi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, Budapest, Hungary
| | - Barbara Uzonyi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, Budapest, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, Budapest, Hungary
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12
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Dahlberg D, Holm S, Sagen EML, Michelsen AE, Stensland M, de Souza GA, Müller EG, Connelly JP, Revheim ME, Halvorsen B, Hassel B. Bacterial Brain Abscesses Expand Despite Effective Antibiotic Treatment: A Process Powered by Osmosis Due to Neutrophil Cell Death. Neurosurgery 2023; 94:00006123-990000000-00996. [PMID: 38084989 PMCID: PMC10990409 DOI: 10.1227/neu.0000000000002792] [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: 09/12/2023] [Accepted: 10/22/2023] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND AND OBJECTIVES A bacterial brain abscess is an emergency and should be drained of pus within 24 hours of diagnosis, as recently recommended. In this cross-sectional study, we investigated whether delaying pus drainage entails brain abscess expansion and what the underlying mechanism might be. METHODS Repeated brain MRI of 47 patients who did not undergo immediate pus drainage, pus osmolarity measurements, immunocytochemistry, proteomics, and 18F-fluorodeoxyglucose positron emission tomography. RESULTS Time from first to last MRI before neurosurgery was 1 to 14 days. Abscesses expanded in all but 2 patients: The median average increase was 23% per day (range 0%-176%). Abscesses expanded during antibiotic therapy and even if the pus did not contain viable bacteria. In a separate patient cohort, we found that brain abscess pus tended to be hyperosmolar (median value 360 mOsm; range 266-497; n = 14; normal cerebrospinal fluid osmolarity is ∼290 mOsm). Hyperosmolarity would draw water into the abscess cavity, causing abscess expansion in a ballooning manner through increased pressure in the abscess cavity. A mechanism likely underlying pus hyperosmolarity was the recruitment of neutrophils to the abscess cavity with ensuing neutrophil cell death and decomposition of neutrophil proteins and other macromolecules to osmolytes: Pus analysis showed the presence of neutrophil proteins (protein-arginine deiminases, citrullinated histone, myeloperoxidase, elastase, cathelicidin). Previous studies have shown very high levels of osmolytes (ammonia, amino acids) in brain abscess pus. 18F-fluorodeoxyglucose positron emission tomography showed focal neocortical hypometabolism 1 to 8 years after brain abscess, indicating long-lasting damage to brain tissue. CONCLUSION Brain abscesses expand despite effective antibiotic treatment. Furthermore, brain abscesses cause lasting damage to surrounding brain tissue. These findings support drainage of brain abscesses within 24 hours of diagnosis.
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Affiliation(s)
- Daniel Dahlberg
- Department of Neurosurgery, Oslo University Hospital, Oslo, Norway
| | - Sverre Holm
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - Ellen Margaret Lund Sagen
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Annika Elisabet Michelsen
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Maria Stensland
- Institute of Immunology and Centre for Immune Regulation, Oslo University Hospital, Oslo, Norway
| | - Gustavo Antonio de Souza
- Institute of Immunology and Centre for Immune Regulation, Oslo University Hospital, Oslo, Norway
- Department of Biochemistry, Universidade Federal Do Rio Grande Do Norte, Natal, Brazil
| | - Ebba Gløersen Müller
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Radiology and Nuclear Medicine, Department of Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - James Patrick Connelly
- Division of Radiology and Nuclear Medicine, Department of Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Mona-Elisabeth Revheim
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Radiology and Nuclear Medicine, Department of Nuclear Medicine, Oslo University Hospital, Oslo, Norway
- The Intervention Centre, Oslo University Hospital, Oslo, Norway
| | - Bente Halvorsen
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Bjørnar Hassel
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Neurohabilitation, Oslo University Hospital, Oslo, Norway
- Norwegian Defence Research Establishment (FFI), Kjeller, Norway
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13
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Drab D, Santocki M, Opydo M, Kolaczkowska E. Impact of endogenous and exogenous nitrogen species on macrophage extracellular trap (MET) formation by bone marrow-derived macrophages. Cell Tissue Res 2023; 394:361-377. [PMID: 37789240 PMCID: PMC10638184 DOI: 10.1007/s00441-023-03832-z] [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: 12/12/2022] [Accepted: 09/26/2023] [Indexed: 10/05/2023]
Abstract
Macrophage extracellular traps (METs) represent a novel defense mechanism in the antimicrobial arsenal of macrophages. However, mechanisms of MET formation are still poorly understood and this is at least partially due to the lack of reliable and reproducible models. Thus, we aimed at establishing a protocol of MET induction by bone marrow-derived macrophages (BMDMs) obtained from cryopreserved and then thawed bone marrow (BM) mouse cells. We report that BMDMs obtained in this way were morphologically (F4/80+) and functionally (expression of inducible nitric oxide (NO) synthase and NO production) differentiated and responded to various stimuli of bacterial (lipopolysaccharide, LPS), fungal (zymosan) and chemical (PMA) origin. Importantly, BMDMs were successfully casting METs composed of extracellular DNA (extDNA) serving as their backbone to which proteins such as H2A.X histones and matrix metalloproteinase 9 (MMP-9) were attached. In rendered 3D structure of METs, extDNA and protein components were embedded in each other. Since studies had shown the involvement of oxygen species in MET release, we aimed at studying if reactive nitrogen species (RNS) such as NO are also involved in MET formation. By application of NOS inhibitor - L-NAME or nitric oxide donor (SNAP), we studied the involvement of endogenous and exogenous RNS in traps release. We demonstrated that L-NAME halted MET formation upon stimulation with LPS while SNAP alone induced it. The latter phenomenon was further enhanced in the presence of LPS. Taken together, our findings demonstrate that BMDMs obtained from cryopreserved BM cells are capable of forming METs in an RNS-dependent manner.
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Affiliation(s)
- Dominika Drab
- Laboratory of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, 30-387, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | - Michal Santocki
- Laboratory of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, 30-387, Krakow, Poland
| | - Malgorzata Opydo
- Laboratory of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, 30-387, Krakow, Poland
| | - Elzbieta Kolaczkowska
- Laboratory of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, 30-387, Krakow, Poland.
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14
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Riehl DR, Sharma A, Roewe J, Murke F, Ruppert C, Eming SA, Bopp T, Kleinert H, Radsak MP, Colucci G, Subramaniam S, Reinhardt C, Giebel B, Prinz I, Guenther A, Strand D, Gunzer M, Waisman A, Ward PA, Ruf W, Schäfer K, Bosmann M. Externalized histones fuel pulmonary fibrosis via a platelet-macrophage circuit of TGFβ1 and IL-27. Proc Natl Acad Sci U S A 2023; 120:e2215421120. [PMID: 37756334 PMCID: PMC10556605 DOI: 10.1073/pnas.2215421120] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
Externalized histones erupt from the nucleus as extracellular traps, are associated with several acute and chronic lung disorders, but their implications in the molecular pathogenesis of interstitial lung disease are incompletely defined. To investigate the role and molecular mechanisms of externalized histones within the immunologic networks of pulmonary fibrosis, we studied externalized histones in human and animal bronchoalveolar lavage (BAL) samples of lung fibrosis. Neutralizing anti-histone antibodies were administered in bleomycin-induced fibrosis of C57BL/6 J mice, and subsequent studies used conditional/constitutive knockout mouse strains for TGFβ and IL-27 signaling along with isolated platelets and cultured macrophages. We found that externalized histones (citH3) were significantly (P < 0.01) increased in cell-free BAL fluids of patients with idiopathic pulmonary fibrosis (IPF; n = 29) as compared to healthy controls (n = 10). The pulmonary sources of externalized histones were Ly6G+CD11b+ neutrophils and nonhematopoietic cells after bleomycin in mice. Neutralizing monoclonal anti-histone H2A/H4 antibodies reduced the pulmonary collagen accumulation and hydroxyproline concentration. Histones activated platelets to release TGFβ1, which signaled through the TGFbRI/TGFbRII receptor complex on LysM+ cells to antagonize macrophage-derived IL-27 production. TGFβ1 evoked multiple downstream mechanisms in macrophages, including p38 MAPK, tristetraprolin, IL-10, and binding of SMAD3 to the IL-27 promotor regions. IL-27RA-deficient mice displayed more severe collagen depositions suggesting that intact IL-27 signaling limits fibrosis. In conclusion, externalized histones inactivate a safety switch of antifibrotic, macrophage-derived IL-27 by boosting platelet-derived TGFβ1. Externalized histones are accessible to neutralizing antibodies for improving the severity of experimental pulmonary fibrosis.
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Affiliation(s)
- Dennis R. Riehl
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Arjun Sharma
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA02118
- Mainz Research School of Translational Biomedicine (TransMed), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Julian Roewe
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Florian Murke
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen45122, Germany
| | - Clemens Ruppert
- Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen35392, Germany
| | - Sabine A. Eming
- Department of Dermatology, University of Cologne, Cologne50931, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne50931, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne50931, Germany
| | - Tobias Bopp
- Institute of Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Hartmut Kleinert
- Department of Pharmacology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz55131, Germany
| | - Markus P. Radsak
- Mainz Research School of Translational Biomedicine (TransMed), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Third Department of Medicine – Hematology, Oncology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Giuseppe Colucci
- Outer Corelab, Viollier AG, Allschwil4123, Switzerland
- Department of Hematology, University of Basel, Basel4031, Switzerland
| | - Saravanan Subramaniam
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA02118
| | - Christoph Reinhardt
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- German Center for Cardiovascular Research, Partner Site Rhine-Main, Mainz55131, Germany
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen45122, Germany
| | - Immo Prinz
- Institute for Immunology, Hannover Medical School, Hannover30625, Germany
| | - Andreas Guenther
- Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen35392, Germany
| | - Dennis Strand
- First Department of Internal Medicine, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz55131, Germany
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen45122, Germany
- Leibniz-Institute for Analytical Sciences -ISAS- e.V., Dortmund44139, Germany
| | - Ari Waisman
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Peter A. Ward
- Department of Pathology, University of Michigan Medical School, Ann Arbor48109, MI
| | - Wolfram Ruf
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Katrin Schäfer
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
| | - Markus Bosmann
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA02118
- Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz55131, Germany
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15
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Teng Y, Chen Y, Tang X, Wang S, Yin K. PAD2: A potential target for tumor therapy. Biochim Biophys Acta Rev Cancer 2023; 1878:188931. [PMID: 37315720 DOI: 10.1016/j.bbcan.2023.188931] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/16/2023]
Abstract
Peptide arginine deiminase 2(PAD2) catalyzes the conversion of arginine residues on target proteins to citrulline residues in the presence of calcium ions. This particular posttranslational modification is called citrullination. PAD2 can regulate the transcriptional activity of genes through histone citrullination and nonhistone citrullination. In this review, we summarize the evidence from recent decades and systematically illustrate the role of PAD2-mediated citrullination in tumor pathology and the regulation of tumor-associated immune cells such as neutrophils, monocytes, macrophages and T cells. Several PAD2-specific inhibitors are also presented to discuss the feasibility of anti-PAD2 therapy to treat tumors and the urgent problems to be solved. Finally, we review some recent developments in the development of PAD2 inhibitors.
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Affiliation(s)
- Yi Teng
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yuhang Chen
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xinyi Tang
- Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Shengjun Wang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China; Department of Laboratory Medicine, the Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
| | - Kai Yin
- Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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16
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Liu Y, Liang J, Li JW, Xing LH, Li FX, Wang N, Wu YJ, Ma YZ, Xing ZR, Jiang X, Zhang XY, Lei ZX, Wang X, Yu SX. Phagocyte extracellular traps formation contributes to host defense against Clostridium perfringens infection. Cytokine 2023; 169:156276. [PMID: 37339556 DOI: 10.1016/j.cyto.2023.156276] [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: 05/03/2022] [Revised: 06/10/2023] [Accepted: 06/12/2023] [Indexed: 06/22/2023]
Abstract
Clostridium perfringens (C. perfringens) is an important Gram-positive anaerobic spore-forming pathogen that provokes life-threatening gas gangrene and acute enterotoxaemia, although it colonizes as a component of the symbiotic bacteria in humans and animals. However, the mechanisms by which C. perfringens is cleared from the host remains poorly understood, thereby impeding the development of novel strategies for control this infection. Here, we uncover a beneficial effect of extracellular traps (ETs) formation on bacterial killing and clearance by phagocytes. C. perfringens strain ATCC13124, and wild-type isolates CP1 and CP3 markedly trigger ETs formation in macrophages and neutrophils. As expected, visualization of DNA decorated with histone, myeloperoxidase (MPO) and neutrophils elastase (NE) in C. perfringens-triggered classical ETs structures. Notably, the bacteria-induced ETs formation is an ERK1/2-, P38 MAPK-, store-operated calcium entry (SOCE)-, NADPH oxidase-, histone-, NE-, and MPO-dependent process, and is independent of LDH activity. Meanwhile, the defect of bactericidal activity is mediated by impairing ETs formation in phagocytes. Moreover, In vivo studies indicated that degradation of ETs by DNase I administration leads to a defect in the protection against experimental gas gangrene, with higher mortality rates, exacerbated tissue damage, and more bacterial colonization. Together, these results suggest that phagocyte ETs formation is essential for the host defense against C. perfringens infection.
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Affiliation(s)
- Yang Liu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China; Animal Husbandry Institute, Agriculture and Animal Husbandry Academy of Inner Mongolia, Hohhot 010031, China
| | - Jing Liang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Jian-Wei Li
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Li-Hua Xing
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Fen-Xin Li
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Na Wang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Yu-Jing Wu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Yu-Ze Ma
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Zhao-Rui Xing
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Xue Jiang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Xin-Yue Zhang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Zheng-Xuan Lei
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Xiao Wang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China.
| | - Shui-Xing Yu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China.
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17
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Goldspink A, Schmitz J, Babyak O, Brauns N, Milleck J, Breloh AM, Fleig SV, Jobin K, Schwarz L, Haller H, Wagenlehner F, Bräsen JH, Kurts C, von Vietinghoff S. Kidney medullary sodium chloride concentrations induce neutrophil and monocyte extracellular DNA traps that defend against pyelonephritis in vivo. Kidney Int 2023:S0085-2538(23)00265-X. [PMID: 37098380 DOI: 10.1016/j.kint.2023.03.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/27/2023]
Abstract
Urinary tract infections are common. Here, we delineate a role of extracellular DNA trap (ET) formation in kidney antibacterial defense and determine mechanisms of their formation in the hyperosmotic environment of the kidney medulla. ET of granulocytic and monocytic origin were present in the kidneys of patients with pyelonephritis along with systemically elevated citrullinated histone levels. Inhibition of the transcription coregulatory, peptidylarginine deaminase 4 (PAD4), required for ET formation, prevented kidney ET formation and promoted pyelonephritis in mice. ETs predominantly accumulated in the kidney medulla. The role of medullary sodium chloride and urea concentrations in ET formation was then investigated. Medullary-range sodium chloride, but not urea, dose-, time- and PAD4-dependently induced ET formation even in the absence of other stimuli. Moderately elevated sodium chloride promoted myeloid cell apoptosis. Sodium gluconate also promoted cell death, proposing a role for sodium ions in this process. Sodium chloride induced myeloid cell calcium influx. Calcium ion-free media or -chelation reduced sodium chloride-induced apoptosis and ET formation while bacterial lipopolysaccharide amplified it. Autologous serum improved bacterial killing in the presence of sodium chloride-induced ET. Depletion of the kidney sodium chloride gradient by loop diuretic therapy diminished kidney medullary ET formation and increased pyelonephritis severity. Thus, our data demonstrate that ETs may protect the kidney against ascending uropathogenic E. coli and delineate kidney medullary range sodium chloride concentrations as novel inducers of programmed myeloid cell death.
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Affiliation(s)
| | | | - Olena Babyak
- Institute of Experimental Immunology, University Clinic and Rheinische Friedrich-Wilhelms Universität Bonn, Bonn
| | - Nicolas Brauns
- Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover
| | | | - Anne M Breloh
- Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover
| | - Susanne V Fleig
- Nephrology Section, First Medical Clinic; Department of Geriatrics, University Hospital RWTH Aachen, Aachen
| | - Katarzyna Jobin
- Institute of Experimental Immunology, University Clinic and Rheinische Friedrich-Wilhelms Universität Bonn, Bonn; Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität, Würzburg
| | - Lisa Schwarz
- Department of Urology, Pediatric Urology and Andrology, Justus Liebig University Giessen, Giessen, Germany
| | - Hermann Haller
- Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover
| | - Florian Wagenlehner
- Department of Urology, Pediatric Urology and Andrology, Justus Liebig University Giessen, Giessen, Germany
| | | | - Christian Kurts
- Institute of Experimental Immunology, University Clinic and Rheinische Friedrich-Wilhelms Universität Bonn, Bonn
| | - Sibylle von Vietinghoff
- Nephrology Section, First Medical Clinic; Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover.
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18
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Jensen M, Thorsen NW, Hallberg LAE, Hägglund P, Hawkins CL. New insight into the composition of extracellular traps released by macrophages exposed to different types of inducers. Free Radic Biol Med 2023; 202:97-109. [PMID: 36990299 DOI: 10.1016/j.freeradbiomed.2023.03.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023]
Abstract
Neutrophil extracellular trap (NET) release plays a key role in many chronic disease settings, including atherosclerosis. They are critical to innate immune defence, but also contribute to disease by promoting thrombosis and inflammation. Macrophages are known to release extracellular traps or "METs", but their composition and role in pathological processes are less well defined. In this study, we examined MET release from human THP-1 macrophages exposed to model inflammatory and pathogenic stimuli, including tumour necrosis factor α (TNFα), hypochlorous acid (HOCl) and nigericin. In each case, there was release of DNA from the macrophages, as visualized by fluorescence microscopy with the cell impermeable DNA binding dye SYTOX green, consistent with MET formation. Proteomic analysis on METs released from macrophages exposed to TNFα and nigericin reveals that they are composed of linker and core histones, together with a range of cytosolic and mitochondrial proteins. These include proteins involved in DNA binding, stress responses, cytoskeletal organisation, metabolism, inflammation, anti-microbial activity, and calcium binding. Quinone oxidoreductase in particular, was highly abundant in all METs but has not been reported previously in NETs. Moreover, there was an absence of proteases in METs in contrast to NETs. Some of the MET histones, contained post-translational modifications, including acetylation and methylation of Lys but not citrullination of Arg. These data provide new insight into the potential implications of MET formation in vivo and their contributions to immune defence and pathology.
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Affiliation(s)
- Mathias Jensen
- Department of Biomedical Sciences, University of Copenhagen, Panum, Blegdamsvej 3B, Copenhagen N, DK-2200, Denmark
| | - Nicoline W Thorsen
- Department of Biomedical Sciences, University of Copenhagen, Panum, Blegdamsvej 3B, Copenhagen N, DK-2200, Denmark
| | - Line A E Hallberg
- Department of Biomedical Sciences, University of Copenhagen, Panum, Blegdamsvej 3B, Copenhagen N, DK-2200, Denmark
| | - Per Hägglund
- Department of Biomedical Sciences, University of Copenhagen, Panum, Blegdamsvej 3B, Copenhagen N, DK-2200, Denmark.
| | - Clare L Hawkins
- Department of Biomedical Sciences, University of Copenhagen, Panum, Blegdamsvej 3B, Copenhagen N, DK-2200, Denmark.
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19
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Michel-Flutot P, Bourcier CH, Emam L, Gasser A, Glatigny S, Vinit S, Mansart A. Extracellular traps formation following cervical spinal cord injury. Eur J Neurosci 2023; 57:692-704. [PMID: 36537022 DOI: 10.1111/ejn.15902] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/20/2022] [Accepted: 12/11/2022] [Indexed: 12/24/2022]
Abstract
Spinal cord injuries involve a primary injury that can lead to permanent loss of function and a secondary injury associated with pathologic and inflammatory processes. Extracellular traps are extracellular structures expressed by immune cells that are primarily composed of chromatin, granular enzymes and histones. Extracellular traps are known to induce tissue damage when overexpressed and could be associated in the occurrence of secondary damage. In the present study, we used flow cytometry to demonstrate that at 1 day following a C2 spinal cord lateral hemisection in male Swiss mice, resident microglia form vital microglia extracellular traps, and infiltrating neutrophils form vital neutrophil extracellular traps. We also used immunolabelling to show that microglia near the lesion area are most likely to form these microglia extracellular traps. As expected, infiltrating neutrophils are located at the site of injury, though only some of them engage in post-injury extracellular trap formation. We also observed the formation of microglia and neutrophil extracellular traps in our sham animal models of durotomy, but formation was less frequent than following the C2 hemisection. Our results demonstrate for the first time that microglia form extracellular traps in the spinal cord following injury and durotomy. It remains however to determine the exact mechanisms and kinetics of neutrophil and microglia extracellular traps formation following spinal cord injury. This information would allow to better mitigate this inflammatory process that may contribute to secondary injury and to effectively target extracellular traps to improve functional outcomes following spinal cord injury.
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Affiliation(s)
| | - Camille H Bourcier
- Université Paris-Saclay, UVSQ, Inserm U1179, END-ICAP, Versailles, France.,Université Paris-Saclay, UVSQ, Inserm U1173, Infection et Inflammation (2I), France
| | - Laila Emam
- Université Paris-Saclay, UVSQ, Inserm U1173, Infection et Inflammation (2I), France
| | - Adeline Gasser
- Université Paris-Saclay, UVSQ, Inserm U1173, Infection et Inflammation (2I), France
| | - Simon Glatigny
- Université Paris-Saclay, UVSQ, Inserm U1173, Infection et Inflammation (2I), France
| | - Stéphane Vinit
- Université Paris-Saclay, UVSQ, Inserm U1179, END-ICAP, Versailles, France
| | - Arnaud Mansart
- Université Paris-Saclay, UVSQ, Inserm U1173, Infection et Inflammation (2I), France
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20
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Kapoor D, Shukla D. Neutrophil Extracellular Traps and Their Possible Implications in Ocular Herpes Infection. Pathogens 2023; 12:209. [PMID: 36839481 PMCID: PMC9958879 DOI: 10.3390/pathogens12020209] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023] Open
Abstract
Neutrophil extracellular traps (NETs) are net-like structures released from neutrophils. NETs predominantly contain cell-free deoxyribonucleic acid (DNA) decorated with histones and neutrophil granule proteins. Numerous extrinsic and intrinsic stimuli can induce the formation of NETs such as pathogens, cytokines, immune complexes, microcrystals, antibodies, and other physiological stimuli. The mechanism of NETosis induction can either be ROS-dependent or independent based on the catalase producing activity of the pathogen. NADPH is the source of ROS production, which in turn depends on the upregulation of Ca2+ production in the cytoplasm. ROS-independent induction of NETosis is regulated through toll-like receptors (TLRs). Besides capturing and eliminating pathogens, NETs also aggravate the inflammatory response and thus act as a double-edged sword. Currently, there are growing reports of NETosis induction during bacterial and fungal ocular infections leading to different pathologies, but there is no direct report suggesting its role during herpes simplex virus (HSV) infection. There are innumerable independent reports showing that the major effectors of NETosis are also directly affected by HSV infection, and thus, there is a strong possibility that HSV interacts with these facilitators that can either result in virally mediated modulation of NETosis or NETosis-mediated suppression of ocular HSV infection. This review focuses on the mechanism of NETs formation during different ocular pathologies, with its prime focus on highlighting their potential implications during HSV ocular infections and acting as prospective targets for the treatment of ocular diseases.
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Affiliation(s)
- Divya Kapoor
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, 1905 W. Taylor St., Chicago, IL 60612, USA
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott, Chicago, IL 60612, USA
| | - Deepak Shukla
- Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, 1905 W. Taylor St., Chicago, IL 60612, USA
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott, Chicago, IL 60612, USA
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21
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Albaladejo-Riad N, Cuesta A, Esteban MÁ. Induction and characterization of extracellular traps by gilthead seabream (Sparus aurata L.) head-kidney leucocytes. FISH & SHELLFISH IMMUNOLOGY 2022; 130:582-590. [PMID: 36152801 DOI: 10.1016/j.fsi.2022.09.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/15/2022] [Accepted: 09/17/2022] [Indexed: 06/16/2023]
Abstract
The aim of this study was the induction and characterization of extracellular traps (ETs) produced by gilthead seabream (Sparus aurata L.) head-kidney leucocytes. The cells were incubated several times (10, 30, 60, 120, and 180 min) with different concentrations of the stimulants diluted in RPMI-1640 culture medium: RPMI-1640 (control), β-glucan from Saccharomyces cerevisiae (BG, 0-400 μg mL-1), lipopolysaccharide from Escherichia coli (LPS, 0-10 μg mL-1), calcium ionophore A23187 (CaI, 0-5 μg mL-1), Phorbol 12-myristate 13-acetate (PMA, 0-1000 ng mL-1) and polyinosinic-polycytidylic acid sodium salt (Poly I:C, 0-200 μg mL-1). BG, LPS and CaI exerted only weak stimulatory activity, while PMA and poly I:C exerted a potent one. After stimulation of the leucocytes, ETs structures were quantified and visualised through staining of the chromatin with nucleic acid-specific dyes and immunocytochemical probing of characteristic proteins expected to decorate the structure. ETs structures had DNA and myeloperoxidase. The ETs morphology was studied by light and scanning electron microscopy. These data confirm that seabream leucocytes form ETs with different morphological properties, depending on the used stimulant. These results will be the basis for new studies to analyse the implication of this mechanism in fish immunity. All this new knowledge will have its application in fish farms when we learn to manipulate the innate immune response in order to mitigate microbial infections.
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Affiliation(s)
- Nora Albaladejo-Riad
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, 30100, Murcia, Spain
| | - Alberto Cuesta
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, 30100, Murcia, Spain
| | - M Ángeles Esteban
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, 30100, Murcia, Spain.
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22
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Olivier FAB, Hilsenstein V, Weerasinghe H, Weir A, Hughes S, Crawford S, Vince JE, Hickey MJ, Traven A. The escape of Candida albicans from macrophages is enabled by the fungal toxin candidalysin and two host cell death pathways. Cell Rep 2022; 40:111374. [PMID: 36130496 DOI: 10.1016/j.celrep.2022.111374] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 06/15/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022] Open
Abstract
The egress of Candida hyphae from macrophages facilitates immune evasion, but it also alerts macrophages to infection and triggers inflammation. To better define the mechanisms, here we develop an imaging assay to directly and dynamically quantify hyphal escape and correlate it to macrophage responses. The assay reveals that Candida escapes by using two pore-forming proteins to permeabilize macrophage membranes: the fungal toxin candidalysin and Nlrp3 inflammasome-activated Gasdermin D. Candidalysin plays a major role in escape, with Nlrp3 and Gasdermin D-dependent and -independent contributions. The inactivation of Nlrp3 does not reduce hyphal escape, and we identify ETosis via macrophage extracellular trap formation as an additional pathway facilitating hyphal escape. Suppressing hyphal escape does not reduce fungal loads, but it does reduce inflammatory activation. Our findings explain how Candida escapes from macrophages by using three strategies: permeabilizing macrophage membranes via candidalysin and engaging two host cell death pathways, Gasdermin D-mediated pyroptosis and ETosis.
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Affiliation(s)
- Françios A B Olivier
- Infection Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800 VIC, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
| | | | - Harshini Weerasinghe
- Infection Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800 VIC, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
| | - Ashley Weir
- The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Sebastian Hughes
- The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Simon Crawford
- Monash Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, VIC 3800, Australia
| | - James E Vince
- The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Michael J Hickey
- Monash Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia
| | - Ana Traven
- Infection Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800 VIC, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia.
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23
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Nofi CP, Wang P, Aziz M. Chromatin-Associated Molecular Patterns (CAMPs) in sepsis. Cell Death Dis 2022; 13:700. [PMID: 35961978 PMCID: PMC9372964 DOI: 10.1038/s41419-022-05155-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 07/28/2022] [Accepted: 08/01/2022] [Indexed: 01/21/2023]
Abstract
Several molecular patterns have been identified that recognize pattern recognition receptors. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are commonly used terminologies to classify molecules originating from pathogen and endogenous molecules, respectively, to heighten the immune response in sepsis. Herein, we focus on a subgroup of endogenous molecules that may be detected as foreign and similarly trigger immune signaling pathways. These chromatin-associated molecules, i.e., chromatin containing nuclear DNA and histones, extracellular RNA, mitochondrial DNA, telomeric repeat-containing RNA, DNA- or RNA-binding proteins, and extracellular traps, may be newly classified as chromatin-associated molecular patterns (CAMPs). Herein, we review the release of CAMPs from cells, their mechanism of action and downstream immune signaling pathways, and targeted therapeutic approaches to mitigate inflammation and tissue injury in inflammation and sepsis.
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Affiliation(s)
- Colleen P. Nofi
- grid.250903.d0000 0000 9566 0634Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY USA ,Elmezi Graduate School of Molecular Medicine, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA
| | - Ping Wang
- grid.250903.d0000 0000 9566 0634Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY USA ,Elmezi Graduate School of Molecular Medicine, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA
| | - Monowar Aziz
- grid.250903.d0000 0000 9566 0634Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY USA ,Elmezi Graduate School of Molecular Medicine, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA ,grid.512756.20000 0004 0370 4759Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY USA
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24
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Yadav P, Trehanpati N, Maiwall R, Sehgal R, Singh R, Islam M, Jagdish RK, Vijayaraghavan R, Maheshwari D, Bhat S, Kale P, Kumar A, Baweja S, Kumar G, Ramakrishna G, Sarin SK. Soluble factors and suppressive monocytes can predict early development of sepsis in acute-on-chronic liver failure. Hepatol Commun 2022; 6:2105-2120. [PMID: 35502507 PMCID: PMC9315131 DOI: 10.1002/hep4.1949] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/22/2022] [Accepted: 03/06/2022] [Indexed: 01/08/2023] Open
Abstract
Patients with acute-on-chronic liver failure (ACLF) have a high probability of developing systemic inflammation and sepsis due to immune dysregulation. Fifty-nine patients with ACLF (12 without and 19 with systemic inflammation, and 28 with sepsis) were serially monitored for clinical and immunological changes at baseline, 6 hours, 24 hours, day 3, and day 7 following hospitalization. Ten healthy controls were also included. At all time points, soluble plasma factors and monocyte functions were studied. Patients with ACLF and systemic inflammation showed higher interleukin (IL)-6, vascular endothelial growth factor-a, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β than patients with no systemic inflammation. Patients with ACLF with sepsis had raised (p < 0.001) levels of IL-1Ra, IL-18, and triggering receptor expressed on myeloid cells 1 (TREM1) compared to patients with ACLF-systemic inflammation. Five of the 19 (26.3%) patients with systemic inflammation developed sepsis within 48-72 hours with a rapid rise in plasma levels of IL-1Ra (1203-35,000 pg/ml), IL-18 (48-114 pg/ml), and TREM1 (1273-4865 pg/ml). Monocytes of patients with ACLF with systemic inflammation and sepsis showed reduced human leukocyte antigen-DR but increased programmed death ligand 1 (PD-L1) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) (p < 0.04) expression with increased ETosis by monocytes at baseline and until day 7. Conclusion: High and rising levels of plasma IL-1Ra, IL-18, TREM1 soluble factors, and increased suppressive monocytes (PDL1+ve , TIM3+ve ) at baseline can stratify patients with ACLF at high risk of developing sepsis within 48-72 hours of hospitalization.
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Affiliation(s)
- Pushpa Yadav
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Nirupama Trehanpati
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Rakhi Maiwall
- 80402Department of HepatologyInstitute of Liver and Biliary SciencesNew DelhiIndia
| | - Rashi Sehgal
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Ravinder Singh
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Mojahidul Islam
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Rakesh Kumar Jagdish
- 80402Department of HepatologyInstitute of Liver and Biliary SciencesNew DelhiIndia
| | - Rajan Vijayaraghavan
- 80402Department of HepatologyInstitute of Liver and Biliary SciencesNew DelhiIndia
| | - Deepanshu Maheshwari
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Sadam Bhat
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Pratibha Kale
- 80402Department of MicrobiologyInstitute of Liver and Biliary SciencesNew DelhiIndia
| | - Anupam Kumar
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Sukriti Baweja
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Guresh Kumar
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Gayatri Ramakrishna
- Laboratory of Molecular ImmunologyDepartment of Molecular and Cellular MedicineInstitute of Liver and Biliary Sciences New DelhiNew DelhiIndia
| | - Shiv K Sarin
- 80402Department of HepatologyInstitute of Liver and Biliary SciencesNew DelhiIndia
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25
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Kim JY, Stevens P, Karpurapu M, Lee H, Englert JA, Yan P, Lee TJ, Pabla N, Pietrzak M, Park GY, Christman JW, Chung S. Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation. Front Immunol 2022; 13:943554. [PMID: 35958610 PMCID: PMC9360579 DOI: 10.3389/fimmu.2022.943554] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
Asthma is phenotypically heterogeneous with several distinctive pathological mechanistic pathways. Previous studies indicate that neutrophilic asthma has a poor response to standard asthma treatments comprising inhaled corticosteroids. Therefore, it is important to identify critical factors that contribute to increased numbers of neutrophils in asthma patients whose symptoms are poorly controlled by conventional therapy. Leukocytes release chromatin fibers, referred to as extracellular traps (ETs) consisting of double-stranded (ds) DNA, histones, and granule contents. Excessive components of ETs contribute to the pathophysiology of asthma; however, it is unclear how ETs drive asthma phenotypes and whether they could be a potential therapeutic target. We employed a mouse model of severe asthma that recapitulates the intricate immune responses of neutrophilic and eosinophilic airway inflammation identified in patients with severe asthma. We used both a pharmacologic approach using miR-155 inhibitor-laden exosomes and genetic approaches using miR-155 knockout mice. Our data show that ETs are present in the bronchoalveolar lavage fluid of patients with mild asthma subjected to experimental subsegmental bronchoprovocation to an allergen and a severe asthma mouse model, which resembles the complex immune responses identified in severe human asthma. Furthermore, we show that miR-155 contributes to the extracellular release of dsDNA, which exacerbates allergic lung inflammation, and the inhibition of miR-155 results in therapeutic benefit in severe asthma mice. Our findings show that targeting dsDNA release represents an attractive therapeutic target for mitigating neutrophilic asthma phenotype, which is clinically refractory to standard care.
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Affiliation(s)
- Ji Young Kim
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Patrick Stevens
- Comprehensive Cancer Center, Biomedical Informatics Shared Resources, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Manjula Karpurapu
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States
| | - Hyunwook Lee
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States
| | - Joshua A. Englert
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States
| | - Pearlly Yan
- Comprehensive Cancer Center, Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Tae Jin Lee
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Navjot Pabla
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Maciej Pietrzak
- Comprehensive Cancer Center, Biomedical Informatics Shared Resources, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Gye Young Park
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - John W. Christman
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States
| | - Sangwoon Chung
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, United States
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26
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Wen X, Xie B, Yuan S, Zhang J. The "Self-Sacrifice" of ImmuneCells in Sepsis. Front Immunol 2022; 13:833479. [PMID: 35572571 PMCID: PMC9099213 DOI: 10.3389/fimmu.2022.833479] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 04/05/2022] [Indexed: 12/15/2022] Open
Abstract
Sepsis is a life-threatening organ dysfunction caused by the host’s malfunctioning response to infection. Due to its high mortality rate and medical cost, sepsis remains one of the world’s most intractable diseases. In the early stage of sepsis, the over-activated immune system and a cascade of inflammation are usually accompanied by immunosuppression. The core pathogenesis of sepsis is the maladjustment of the host’s innate and adaptive immune response. Many immune cells are involved in this process, including neutrophils, mononuclear/macrophages and lymphocytes. The immune cells recognize pathogens, devour pathogens and release cytokines to recruit or activate other cells in direct or indirect manner. Pyroptosis, immune cell-extracellular traps formation and autophagy are several novel forms of cell death that are different from apoptosis, which play essential roles in the progress of sepsis. Immune cells can initiate “self-sacrifice” through the above three forms of cell death to protect or kill pathogens. However, the exact roles and mechanisms of the self-sacrifice in the immune cells in sepsis are not fully elucidated. This paper mainly analyzes the self-sacrifice of several representative immune cells in the forms of pyroptosis, immune cell-extracellular traps formation and autophagy to reveal the specific roles they play in the occurrence and progression of sepsis, also to provide inspiration and references for further investigation of the roles and mechanisms of self-sacrifice of immune cells in the sepsis in the future, meanwhile, through this work, we hope to bring inspiration to clinical work.
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Affiliation(s)
- Xiaoyue Wen
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bing Xie
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiying Yuan
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiancheng Zhang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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27
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Cutaneous Wound Healing: A Review about Innate Immune Response and Current Therapeutic Applications. Mediators Inflamm 2022; 2022:5344085. [PMID: 35509434 PMCID: PMC9061066 DOI: 10.1155/2022/5344085] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 12/22/2021] [Accepted: 03/25/2022] [Indexed: 12/22/2022] Open
Abstract
Skin wounds and compromised wound healing are major concerns for the public. Although skin wound healing has been studied for decades, the molecular and cellular mechanisms behind the process are still not completely clear. The systemic responses to trauma involve the body’s inflammatory and immunomodulatory cellular and humoral networks. Studies over the years provided essential insights into a complex and dynamic immunity during the cutaneous wound healing process. This review will focus on innate cell populations involved in the initial phase of this orchestrated process, including innate cells from both the skin and the immune system.
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28
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Guo L, Shen J, Lei W, Yan P, Wang M, Zhou Q, Wang H, Wu J, Chen J, Wang R. Plasma Donor-Derived Cell-Free DNA Levels Are Associated With the Inflammatory Burden and Macrophage Extracellular Trap Activity in Renal Allografts. Front Immunol 2022; 13:796326. [PMID: 35386710 PMCID: PMC8977515 DOI: 10.3389/fimmu.2022.796326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 02/22/2022] [Indexed: 11/23/2022] Open
Abstract
Recent studies have confirmed the role of plasma donor-derived cell-free DNA (ddcfDNA) as a reliable non-invasive biomarker for allograft injury after kidney transplantation. Whereas the variability of plasma ddcfDNA levels among recipients has limited their clinical use. This study aimed to explore the intrinsic factors associated with plasma ddcfDNA elevation by investigating the impact of Banff lesions and inflammatory infiltrates on ddcfDNA levels in kidney transplant recipients. From March 2017 to September 2019, a total of 106 kidney transplant recipients with matched allograft biopsies were included, consisting of 13 recipients with normal/nonspecific changes, 13 recipients with borderline changes, 60 with T cell-mediated rejection, and 20 with antibody-mediated rejection. Histologic classification was performed according to the Banff 2017 criteria by two experienced pathologists. Plasma ddcfDNA fractions ranged from 0.12% to 10.22%, with a median level of 0.91%. Banff histology subelements including glomerulitis, intimal arteritis, and severe interstitial inflammation were correlated with increased plasma ddcfDNA levels. The inflammatory cell infiltrate in the allografts was phenotyped by immunochemistry and automatically counted by digital image recognition. Pearson correlation analysis revealed a significant positive correlation between macrophage infiltrations in allografts and plasma ddcfDNA levels. Additionally, macrophage extracellular trap (MET) activity was significantly associated with the rise in plasma ddcfDNA levels. Our findings demonstrated that plasma ddcfDNA could reflect the inflammatory state in renal allografts and suggested the potential role of METs in the pathogenesis of allograft injury.
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Affiliation(s)
- Luying Guo
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Jia Shen
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Wenhua Lei
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Pengpeng Yan
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Meifang Wang
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Qin Zhou
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Huiping Wang
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Jianyong Wu
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
| | - Rending Wang
- Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.,National Key Clinical Department of Kidney Diseases, Hangzhou, China.,Institute of Nephrology, Zhejiang University, Hangzhou, China.,Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
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29
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Role of macrophage extracellular traps in innate immunity and inflammatory disease. Biochem Soc Trans 2022; 50:21-32. [PMID: 35191493 DOI: 10.1042/bst20210962] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
Macrophages play an integral role in initiating innate immune defences and regulating inflammation. They are also involved in maintaining homeostasis and the resolution of inflammation, by promoting tissue repair and wound healing. There is evidence that like neutrophils, macrophages can release extracellular traps following exposure to a range of pathogenic and pro-inflammatory stimuli. Extracellular traps are released by a specialised cell death pathway termed 'ETosis', and consist of a backbone of DNA and histones decorated with a range of other proteins. The composition of extracellular trap proteins can be influenced by both the cell type and the local environment in which the traps are released. In many cases, these proteins have an antimicrobial role and assist with pathogen killing. Therefore, the release of extracellular traps serves as a means to both immobilise and destroy invading pathogens. In addition to their protective role, extracellular traps are also implicated in disease pathology. The release of neutrophil extracellular traps (NETs) is causally linked to the development of wide range of human diseases. However, whether macrophage extracellular traps (METs) play a similar role in disease pathology is less well established. Moreover, macrophages are also involved in the clearance of extracellular traps, which could assist in the resolution of tissue damage associated with the presence of extracellular traps. In this review, we will provide an overview of the pathways responsible for macrophage extracellular trap release, and discuss the role of these structures in innate immunity and disease pathology and possible therapeutic strategies.
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30
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Weng W, Hu Z, Pan Y. Macrophage Extracellular Traps: Current Opinions and the State of Research regarding Various Diseases. J Immunol Res 2022; 2022:7050807. [PMID: 35036449 PMCID: PMC8759907 DOI: 10.1155/2022/7050807] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022] Open
Abstract
Macrophages are an important component of the human immune system and play a key role in the immune response, which can protect the body against infection and regulate the development of tissue inflammation. Some studies found that macrophages can produce extracellular traps (ETs) under various conditions of stimulation. ETs are web-like structures that consist of proteins and DNA. ETs are thought to immobilize and kill microorganisms, as well as play an important role in tissue damage, inflammatory progression, and autoimmune diseases. In this review, the structure, identification, mechanism, and research progress of macrophage extracellular traps (METs) in related diseases are reviewed.
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Affiliation(s)
- Weizhen Weng
- Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Zuoyu Hu
- Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
| | - Yunfeng Pan
- Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China
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31
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Lee Y, Reilly B, Tan C, Wang P, Aziz M. Extracellular CIRP Induces Macrophage Extracellular Trap Formation Via Gasdermin D Activation. Front Immunol 2021; 12:780210. [PMID: 35003095 PMCID: PMC8732379 DOI: 10.3389/fimmu.2021.780210] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 12/03/2021] [Indexed: 01/03/2023] Open
Abstract
Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern promoting inflammation and tissue injury. During bacterial or viral infection, macrophages release DNA decorated with nuclear and cytoplasmic proteins known as macrophage extracellular traps (METs). Gasdermin D (GSDMD) is a pore-forming protein that has been involved in extracellular trap formation in neutrophils. We hypothesized that eCIRP induces MET formation by activating GSDMD. Human monocytic cell line THP-1 cells were differentiated with phorbol 12-myristate 13-acetate (PMA) and treated with recombinant murine (rm) CIRP. The MET formation was detected by three methods: time-lapse fluorescence microscopy (video imaging), colorimetry, and ELISA. Cleaved forms of GSDMD, and caspase-1 were detected by Western blotting. Treatment of THP-1 cells with rmCIRP increased MET formation as revealed by SYTOX Orange Staining assay in a time- and dose-dependent manner. METs formed by rmCIRP stimulation were further confirmed by extracellular DNA, citrullinated histone H3, and myeloperoxidase. Treatment of THP-1 cells with rmCIRP significantly increased the cleaved forms of caspase-1 and GSDMD compared to PBS-treated cells. Treatment of macrophages with caspase-1, and GSDMD inhibitors z-VAD-fmk, and disulfiram, separately, significantly decreased rmCIRP-induced MET formation. We also confirmed rmCIRP-induced MET formation using primary cells murine peritoneal macrophages. These data clearly show that eCIRP serves as a novel inducer of MET formation through the activation of GSDMD and caspase-1.
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Affiliation(s)
- Yongchan Lee
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Bridgette Reilly
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Chuyi Tan
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
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32
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Álvarez de Haro N, Van AP, Robb CT, Rossi AG, Desbois AP. Release of chromatin extracellular traps by phagocytes of Atlantic salmon, Salmo salar (Linnaeus, 1758). FISH & SHELLFISH IMMUNOLOGY 2021; 119:209-219. [PMID: 34438058 PMCID: PMC8653909 DOI: 10.1016/j.fsi.2021.08.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/18/2021] [Accepted: 08/22/2021] [Indexed: 05/05/2023]
Abstract
Neutrophils release chromatin extracellular traps (ETs) as part of the fish innate immune response to counter the threats posed by microbial pathogens. However, relatively little attention has been paid to this phenomenon in many commercially farmed species, despite the importance of understanding host-pathogen interactions and the potential to influence ET release to reduce disease outbreaks. The aim of this present study was to investigate the release of ETs by Atlantic salmon (Salmo salar L.) immune cells. Extracellular structures resembling ETs of different morphology were observed by fluorescence microscopy in neutrophil suspensions in vitro, as these structures stained positively with Sytox Green and were digestible with DNase I. Immunofluorescence studies confirmed the ET structures to be decorated with histones H1 and H2A and neutrophil elastase, which are characteristic for ETs in mammals and other organisms. Although the ETs were released spontaneously, release in neutrophil suspensions was stimulated most significantly with 5 μg/ml calcium ionophore (CaI) for 1 h, whilst the fish pathogenic bacterium Aeromonas salmonicida (isolates 30411 and Hooke) also exerted a stimulatory effect. Microscopic observations revealed bacteria in association with ETs, and fewer bacterial colonies of A. salmonicida Hooke were recovered at 3 h after co-incubation with neutrophils that had been induced to release ETs. Interestingly, spontaneous release of ETs was inversely associated with fish mass (p < 0.05), a surrogate for age. Moreover, suspensions enriched for macrophages and stimulated with 5 μg/ml CaI released ET-like structures that occasionally led to the formation of large clumps of cells. A deeper understanding for the roles and functions of ETs within innate immunity of fish hosts, and their interaction with microbial pathogens, may open new avenues towards protecting cultured stocks against infectious diseases.
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Affiliation(s)
- Neila Álvarez de Haro
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling, FK9 4LA, United Kingdom
| | - Andre P Van
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling, FK9 4LA, United Kingdom
| | - Calum T Robb
- University of Edinburgh, Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom
| | - Adriano G Rossi
- University of Edinburgh, Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom
| | - Andrew P Desbois
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling, FK9 4LA, United Kingdom.
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33
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Wu Z, Li P, Tian Y, Ouyang W, Ho JWY, Alam HB, Li Y. Peptidylarginine Deiminase 2 in Host Immunity: Current Insights and Perspectives. Front Immunol 2021; 12:761946. [PMID: 34804050 PMCID: PMC8599989 DOI: 10.3389/fimmu.2021.761946] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/20/2021] [Indexed: 11/13/2022] Open
Abstract
Peptidylarginine deiminases (PADs) are a group of enzymes that catalyze post-translational modifications of proteins by converting arginine residues into citrullines. Among the five members of the PAD family, PAD2 and PAD4 are the most frequently studied because of their abundant expression in immune cells. An increasing number of studies have identified PAD2 as an essential factor in the pathogenesis of many diseases. The successes of preclinical research targeting PAD2 highlights the therapeutic potential of PAD2 inhibition, particularly in sepsis and autoimmune diseases. However, the underlying mechanisms by which PAD2 mediates host immunity remain largely unknown. In this review, we will discuss the role of PAD2 in different types of cell death signaling pathways and the related immune disorders contrasted with functions of PAD4, providing novel therapeutic strategies for PAD2-associated pathology.
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Affiliation(s)
- Zhenyu Wu
- Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, United States,Department of Infectious Diseases, Xiangya 2 Hospital, Central South University, Changsha, China
| | - Patrick Li
- Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, United States,Department of Internal Medicine, New York University (NYU) Langone Health, New York, NY, United States
| | - Yuzi Tian
- Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, United States,Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, China
| | - Wenlu Ouyang
- Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, United States,Department of Infectious Diseases, Xiangya 2 Hospital, Central South University, Changsha, China
| | - Jessie Wai-Yan Ho
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Hasan B. Alam
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Yongqing Li
- Department of Surgery, University of Michigan Hospital, Ann Arbor, MI, United States,*Correspondence: Yongqing Li,
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34
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Kárpáti É, Kremlitzka M, Sándor N, Hajnal D, Schneider AE, Józsi M. Complement Factor H Family Proteins Modulate Monocyte and Neutrophil Granulocyte Functions. Front Immunol 2021; 12:660852. [PMID: 34671340 PMCID: PMC8521052 DOI: 10.3389/fimmu.2021.660852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 09/07/2021] [Indexed: 01/13/2023] Open
Abstract
Besides being a key effector arm of innate immunity, a plethora of non-canonical functions of complement has recently been emerging. Factor H (FH), the main regulator of the alternative pathway of complement activation, has been reported to bind to various immune cells and regulate their functions, beyond its role in modulating complement activation. In this study we investigated the effect of FH, its alternative splice product FH-like protein 1 (FHL-1), the FH-related (FHR) proteins FHR-1 and FHR-5, and the recently developed artificial complement inhibitor mini-FH, on two key innate immune cells, monocytes and neutrophilic granulocytes. We found that, similar to FH, the other factor H family proteins FHL-1, FHR-1 and FHR-5, as well as the recombinant mini-FH, are able to bind to both monocytes and neutrophils. As a functional outcome, immobilized FH and FHR-1 inhibited PMA-induced NET formation, but increased the adherence and IL-8 production of neutrophils. FHL-1 increased only the adherence of the cells, while FHR-5 was ineffective in altering these functions. The adherence of monocytes was increased on FH, recombinant mini-FH and FHL-1 covered surfaces and, except for FHL-1, the same molecules also enhanced secretion of the inflammatory cytokines IL-1β and TNFα. When monocytes were stimulated with LPS in the presence of immobilized FH family proteins, FH, FHL-1 and mini-FH enhanced whereas FHR-1 and FHR-5 decreased the secretion of TNFα; FHL-1 and mini-FH also enhanced IL-10 release compared to the effect of LPS alone. Our results reveal heterogeneous effects of FH and FH family members on monocytes and neutrophils, altering key features involved in pathogen killing, and also demonstrate that FH-based complement inhibitors, such as mini-FH, may have effects beyond their function of inhibiting complement activation. Thus, our data provide new insight into the non-canonical functions of FH, FHL-1, FHR-1 and FHR-5 that might be exploited during protection against infections and in vaccine development.
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Affiliation(s)
- Éva Kárpáti
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Mariann Kremlitzka
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Noémi Sándor
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Eötvös Loránd Research Network (ELKH), Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Dávid Hajnal
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Andrea E Schneider
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Eötvös Loránd Research Network (ELKH), Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
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35
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Wier E, Asada M, Wang G, Alphonse MP, Li A, Hintelmann C, Sweren E, Youn C, Pielstick B, Ortines R, Lyu C, Daskam M, Miller LS, Archer NK, Garza LA. Neutrophil extracellular traps impair regeneration. J Cell Mol Med 2021; 25:10008-10019. [PMID: 34623736 PMCID: PMC8572775 DOI: 10.1111/jcmm.16896] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 01/04/2023] Open
Abstract
Fibrosis is a major health burden across diseases and organs. To remedy this, we study wound‐induced hair follicle neogenesis (WIHN) as a model of non‐fibrotic healing that recapitulates embryogenesis for de novo hair follicle morphogenesis after wounding. We previously demonstrated that TLR3 promotes WIHN through binding wound‐associated dsRNA, the source of which is still unclear. Here, we find that multiple distinct contexts of high WIHN all show a strong neutrophil signature. Given the correlation between neutrophil infiltration and endogenous dsRNA release, we hypothesized that neutrophil extracellular traps (NETs) likely release nuclear spliceosomal U1 dsRNA and modulate WIHN. However, rather than enhance regeneration, we find mature neutrophils inhibit WIHN such that mice with mature neutrophil depletion exhibit higher WIHN. Similarly, Pad4 null mice, which are defective in NET production, show augmented WIHN. Finally, using single‐cell RNA sequencing, we identify a dramatic increase in mature and activated neutrophils in the wound beds of low regenerating Tlr3−/− mice. Taken together, these results demonstrate that although mature neutrophils are stimulated by a common pro‐regenerative cue, their presence and NETs hinder regeneration.
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Affiliation(s)
- Eric Wier
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mayumi Asada
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Gaofeng Wang
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China
| | - Martin P Alphonse
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ang Li
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Chase Hintelmann
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Evan Sweren
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christine Youn
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Brittany Pielstick
- Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore, Maryland, USA
| | - Roger Ortines
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Chenyi Lyu
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Maria Daskam
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lloyd S Miller
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Immunology, Janssen Research and Development, Spring House, PA, USA
| | - Nathan K Archer
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Luis A Garza
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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36
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Kummarapurugu AB, Zheng S, Ma J, Ghosh S, Hawkridge A, Voynow JA. Neutrophil Elastase Triggers the Release of Macrophage Extracellular Traps: Relevance to CF. Am J Respir Cell Mol Biol 2021; 66:76-85. [PMID: 34597246 DOI: 10.1165/rcmb.2020-0410oc] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Neutrophil extracellular traps increase cystic fibrosis (CF) airway inflammation. We hypothesized that macrophage exposure to neutrophil elastase (NE) would trigger the release of macrophage extracellular traps (METs), a novel mechanism to augment NE-induced airway inflammation in CF. To test whether human blood monocyte derived macrophages (hBMDM) from CF and non-CF subjects take up proteolytically active NE resulting in clipping of chromatin binding proteins and the release of METs. Human BMDM from CF and non-CF subjects were treated with FITC-NE to determine NE localization. Intracellular NE activity was determined by DQ-elastin assay. MET DNA release was detected by Pico-green for hBMDM, and visualized by confocal microscopy for hBMDM, and for alveolar macrophages harvested from intratracheal NE-exposed Cftr-null and wild-type littermate mice. Immunofluorescence assays for histone citrullination and western analyses for histone clipping were performed. FITC-NE was localized to cytoplasmic and nuclear domains, and NE retained proteolytic activity in hBMDM. NE (100 to 500 nM) significantly increased extracellular DNA release from hBMDM. NE activated MET release by confocal microscopy in hBMDM, and in alveolar macrophages from Cftr-null and Cftr wild-type mice. NE-triggered MET release was associated with H3 citrullination and partial cleavage of Histone H3 but not H4. Exposure to NE caused release of METs from both CF and non-CF hBMDM in vitro and murine alveolar macrophages in vivo. MET release was associated with NE-activated H3 clipping, a mechanism associated with chromatin decondensation, a prerequisite for METs.
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Affiliation(s)
- Apparao B Kummarapurugu
- Children's Hospital of Richmond at Virginia Commonwealth University, 480853, Pediatric Pulmonology, Richmond, Virginia, United States;
| | - Shuo Zheng
- Children's Hospital of Richmond at VCU, 480853, Pediatric Pulmonology, Richmond, Virginia, United States
| | - Jonathan Ma
- Virginia Commonwealth University Department of Pediatrics, 466504, Richmond, Virginia, United States
| | - Shobha Ghosh
- Virginia Commonwealth University Department of Internal Medicine, 122693, Richmond, Virginia, United States
| | - Adam Hawkridge
- Virginia Commonwealth University School of Pharmacy, 15535, Richmond, Virginia, United States
| | - Judith A Voynow
- Children's Hospital of Richmond at VCU, 480853, Division of Pediatric Pulmonology, Richmond, Virginia, United States
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37
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Payne JAE, Kulkarni K, Izore T, Fulcher AJ, Peleg AY, Aguilar MI, Cryle MJ, Del Borgo MP. Staphylococcus aureus entanglement in self-assembling β-peptide nanofibres decorated with vancomycin. NANOSCALE ADVANCES 2021; 3:2607-2616. [PMID: 36134162 PMCID: PMC9419598 DOI: 10.1039/d0na01018a] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/23/2021] [Indexed: 06/16/2023]
Abstract
The increasing resistance of pathogenic microbes to antimicrobials and the shortage of antibiotic drug discovery programs threaten the clinical use of antibiotics. This threat calls for the development of new methods for control of drug-resistant microbial pathogens. We have designed, synthesised and characterised an antimicrobial material formed via the self-assembly of a population of two distinct β-peptide monomers, a lipidated tri-β-peptide (β3-peptide) and a novel β3-peptide conjugated to a glycopeptide antibiotic, vancomycin. The combination of these two building blocks resulted in fibrous assemblies with distinctive structures determined by atomic force microscopy and electron microscopy. These fibres inhibited the growth of methicillin resistant Staphylococcus aureus (MRSA) and associated directly with the bacteria, acting as a peptide nanonet with fibre nucleation sites on the bacteria observed by electron microscopy and confocal microscopy. Our results provide insights into the design of peptide based supramolecular assemblies with antibacterial activity and establish an innovative strategy to develop self-assembled antimicrobial materials for future biomedical application.
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Affiliation(s)
- Jennifer A E Payne
- Infection and Immunity Program, The Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University Clayton Victoria 3800 Australia
- EMBL Australia, Monash University Clayton Victoria 3800 Australia
- The ARC Centre of Excellence for Innovations in Peptide and Protein Science, Monash University Clayton Victoria 3800 Australia
| | - Ketav Kulkarni
- Department of Biochemistry and Molecular Biology, Monash University Clayton Victoria 3800 Australia
| | - Thierry Izore
- Infection and Immunity Program, The Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University Clayton Victoria 3800 Australia
- EMBL Australia, Monash University Clayton Victoria 3800 Australia
| | - Alex J Fulcher
- Monash Micro Imaging, Monash University Clayton Victoria 3800 Australia
| | - Anton Y Peleg
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University Clayton Victoria 3800 Australia
- Department of Infectious Diseases, The Alfred Hospital, Central Clinical School, Monash University Melbourne Victoria 3004 Australia
| | - Marie-Isabel Aguilar
- Department of Biochemistry and Molecular Biology, Monash University Clayton Victoria 3800 Australia
| | - Max J Cryle
- Infection and Immunity Program, The Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University Clayton Victoria 3800 Australia
- EMBL Australia, Monash University Clayton Victoria 3800 Australia
- The ARC Centre of Excellence for Innovations in Peptide and Protein Science, Monash University Clayton Victoria 3800 Australia
| | - Mark P Del Borgo
- Department of Pharmacology, Monash University Clayton Victoria 3800 Australia
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38
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Bruggeman Y, Sodré FMC, Buitinga M, Mathieu C, Overbergh L, Kracht MJL. Targeting citrullination in autoimmunity: insights learned from preclinical mouse models. Expert Opin Ther Targets 2021; 25:269-281. [PMID: 33896351 DOI: 10.1080/14728222.2021.1918104] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Aberrant citrullination and excessive peptidylarginine deiminase (PAD) activity are detected in numerous challenging autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes. Because excessive PAD activity is a common denominator in these diseases, PADs are interesting potential therapeutic targets for future therapies. AREAS COVERED This review summarizes the advances made in the design of PAD inhibitors, their utilization and therapeutic potential in preclinical mouse models of autoimmunity. Relevant literature encompasses studies from 1994 to 2021 that are available on PubMed.gov. EXPERT OPINION Pan-PAD inhibition is a promising therapeutic strategy for autoimmune diseases. Drugs achieving pan-PAD inhibition were capable of ameliorating, reversing, and preventing clinical symptoms in preclinical mouse models. However, the implications for PADs in key biological processes potentially present a high risk for clinical complications and could hamper the translation of PAD inhibitors to the clinic. We envisage that PAD isozyme-specific inhibitors will improve the understanding the role of PAD isozymes in disease pathology, reduce the risk of side-effects and enhance prospects for future clinical translation.
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Affiliation(s)
- Ylke Bruggeman
- Department of Chronic Diseases and Metabolism, Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
| | - Fernanda M C Sodré
- Department of Chronic Diseases and Metabolism, Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
| | - Mijke Buitinga
- Department of Chronic Diseases and Metabolism, Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.,Department of Nutrition and Movement Sciences, Maastricht University, Maastricht, The Netherlands.,Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Chantal Mathieu
- Department of Chronic Diseases and Metabolism, Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
| | - Lut Overbergh
- Department of Chronic Diseases and Metabolism, Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
| | - Maria J L Kracht
- Department of Chronic Diseases and Metabolism, Laboratory for Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
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Sepand MR, Aghsami M, Keshvadi MH, Bigdelou B, Behzad R, Zanganeh S, Shadboorestan A. The role of macrophage polarization and function in environmental toxicant-induced cancers. ENVIRONMENTAL RESEARCH 2021; 196:110933. [PMID: 33689818 DOI: 10.1016/j.envres.2021.110933] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 02/10/2021] [Accepted: 02/20/2021] [Indexed: 06/12/2023]
Abstract
Macrophages are a critical member of the innate immune system and can intensify tumor invasiveness and assist the growth of neoplastic cells. Moreover, they have the capability to reinforce immunosuppression and angiogenesis. Various investigations suggest that health-related issues, including inflammatory disorders and neoplastic diseases may be caused by environmental toxicant exposure. However, it is still unclear what role these environmental toxicants play in causing carcinogenesis by disturbing the mechanisms of migration, polarization, differentiation, and immune-stimulatory functions of macrophages. Accordingly, in this article, we will explore the interaction between environmental chemicals and inflammatory macrophage processes at the molecular level and their association with tumor progression and carcinogenesis.
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Affiliation(s)
- Mohammad Reza Sepand
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, Dartmouth, MA, 02747, USA
| | - Mehdi Aghsami
- Department of Pharmacology and Toxicology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Keshvadi
- Department of Pharmacology and Toxicology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
| | - Banafsheh Bigdelou
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, Dartmouth, MA, 02747, USA
| | - Ramina Behzad
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, Dartmouth, MA, 02747, USA
| | - Steven Zanganeh
- Department of Bioengineering, University of Massachusetts Dartmouth, 285 Old Westport Road, Dartmouth, MA, 02747, USA.
| | - Amir Shadboorestan
- Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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Williams TJ, Gonzales-Huerta LE, Armstrong-James D. Fungal-Induced Programmed Cell Death. J Fungi (Basel) 2021; 7:jof7030231. [PMID: 33804601 PMCID: PMC8003624 DOI: 10.3390/jof7030231] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 01/01/2023] Open
Abstract
Fungal infections are a cause of morbidity in humans, and despite the availability of a range of antifungal treatments, the mortality rate remains unacceptably high. Although our knowledge of the interactions between pathogenic fungi and the host continues to grow, further research is still required to fully understand the mechanism underpinning fungal pathogenicity, which may provide new insights for the treatment of fungal disease. There is great interest regarding how microbes induce programmed cell death and what this means in terms of the immune response and resolution of infection as well as microbe-specific mechanisms that influence cell death pathways to aid in their survival and continued infection. Here, we discuss how programmed cell death is induced by fungi that commonly cause opportunistic infections, including Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, the role of programmed cell death in fungal immunity, and how fungi manipulate these pathways.
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Ladero-Auñon I, Molina E, Holder A, Kolakowski J, Harris H, Urkitza A, Anguita J, Werling D, Elguezabal N. Bovine Neutrophils Release Extracellular Traps and Cooperate With Macrophages in Mycobacterium avium subsp. paratuberculosis clearance In Vitro. Front Immunol 2021; 12:645304. [PMID: 33815401 PMCID: PMC8010319 DOI: 10.3389/fimmu.2021.645304] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/25/2021] [Indexed: 12/19/2022] Open
Abstract
Mycobacterium avium subsp. paratuberculosis (Map) is the underlying pathogen causing bovine paratuberculosis (PTB), an enteric granulomatous disease that mainly affects ruminants and for which an effective treatment is needed. Macrophages are the primary target cells for Map, which survives and replicates intracellularly by inhibiting phagosome maturation. Neutrophils are present at disease sites during the early stages of the infection, but seem to be absent in the late stage, in contrast to healthy tissue. Although neutrophil activity has been reported to be impaired following Map infection, their role in PTB pathogenesis has not been fully defined. Neutrophils are capable of releasing extracellular traps consisting of extruded DNA and proteins that immobilize and kill microorganisms, but this mechanism has not been evaluated against Map. Our main objective was to study the interaction of neutrophils with macrophages during an in vitro mycobacterial infection. For this purpose, neutrophils and macrophages from the same animal were cultured alone or together in the presence of Map or Mycobacterium bovis Bacillus-Calmette-Guérin (BCG). Extracellular trap release, mycobacteria killing as well as IL-1β and IL-8 release were assessed. Neutrophils released extracellular traps against mycobacteria when cultured alone and in the presence of macrophages without direct cell contact, but resulted inhibited in direct contact. Macrophages were extremely efficient at killing BCG, but ineffective at killing Map. In contrast, neutrophils showed similar killing rates for both mycobacteria. Co-cultures infected with Map showed the expected killing effect of combining both cell types, whereas co-cultures infected with BCG showed a potentiated killing effect beyond the expected one, indicating a potential synergistic cooperation. In both cases, IL-1β and IL-8 levels were lower in co-cultures, suggestive of a reduced inflammatory reaction. These data indicate that cooperation of both cell types can be beneficial in terms of decreasing the inflammatory reaction while the effective elimination of Map can be compromised. These results suggest that neutrophils are effective at Map killing and can exert protective mechanisms against Map that seem to fail during PTB disease after the arrival of macrophages at the infection site.
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Affiliation(s)
- Iraia Ladero-Auñon
- Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development-Basque Research and Technology Allianca (BRTA), Derio, Spain.,Food Quality and Safety Department, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Vitoria-Gasteiz, Spain
| | - Elena Molina
- Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development-Basque Research and Technology Allianca (BRTA), Derio, Spain
| | - Angela Holder
- Molecular Immunology Laboratory, Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, United Kingdom
| | - Jeannine Kolakowski
- Molecular Immunology Laboratory, Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, United Kingdom
| | - Heather Harris
- Food Quality and Safety Department, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Vitoria-Gasteiz, Spain
| | | | - Juan Anguita
- Inflammation and Macrophage Plasticity Laboratory, Centro de Investigaciones Cooperativas (CIC) bioGUNE-Basque Research and Technology Alliance (BRTA), Derio, Spain.,Basque Foundation for Science, Bilbao, Spain
| | - Dirk Werling
- Molecular Immunology Laboratory, Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, United Kingdom
| | - Natalia Elguezabal
- Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development-Basque Research and Technology Allianca (BRTA), Derio, Spain
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Han Y, Chen L, Zhang Q, Yu D, Yang D, Zhao J. Hemocyte extracellular traps of Manila clam Ruditapes philippinarum: Production characteristics and antibacterial effects. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 116:103953. [PMID: 33275994 DOI: 10.1016/j.dci.2020.103953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 06/12/2023]
Abstract
Extracellular traps (ETs) have been found to be an important strategy of mammals to immobilize and kill invading microorganisms. In the present study, we observed the formation of ETs in the hemocytes of marine mollusks Ruditapes philippinarum in response to challenge from bacteria Vibrio anguillarum, and examined the potential factors and signaling pathways underling this process. We detected an increase of reactive oxygen species (ROS) and myeloperoxidase (MPO) production during ETosis, accompanied by significantly up-regulated expression of ROS-related and MPO genes. The suppression of ETs structures by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (diphenyleneiodonium chloride, DPI) and MPO inhibitor (aminobenzoic acid hydrazide, ABAH) further confirmed the essential roles ROS and MPO played in ETosis. Furthermore, ET production could be inhibited by phosphotidylinsitol-3-kinase (PI3K) inhibitor (LY294002) and extracellular regulated protein kinase (ERK) inhibitor (U0126), suggesting the idea that both the PI3K and ERK pathways were suggested to function during ETosis. In addition, the ETosis process was accompanied by enhancement of glycolysis-related enzymatic activities, e.g., pyruvate kinase (PK) and hexokinase (HK), and over-expression of the glycolysis-related genes, e.g., PK, HK and glucose transport protein (GLUT), indicating high involvement of glycolysis in the ETosis process. Furthermore, our scanning electron microscopy (SEM) observation and antibacterial activities test successfully showed the patterns how clam ETs entrapped and killed the invading V. anguillarum. Taken together, our results revealed that ETosis with bactericidal effect increased ROS, MPO and glycolysis level and carried out in a ROS-, MPO-, PI3K-ERK-dependent manner.
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Affiliation(s)
- Yijing Han
- Muping Coastal Environment Research Station, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, PR China; Research and Development Center for Efficient Utilization of Coastal Bioresources, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, PR China; Center for Ocean Mega-science, Chinese Academy of Sciences, Qingdao, Shandong, 266071, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Lizhu Chen
- Shandong Marine Resource and Environment Research Institute, Yantai, 264006, PR China
| | - Qianqian Zhang
- Muping Coastal Environment Research Station, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, PR China; Research and Development Center for Efficient Utilization of Coastal Bioresources, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, PR China; Center for Ocean Mega-science, Chinese Academy of Sciences, Qingdao, Shandong, 266071, PR China
| | - Daode Yu
- Marine Biology Institute of Shandong Province, Qingdao, Shandong, 266002, PR China
| | - Dinglong Yang
- Muping Coastal Environment Research Station, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, PR China; Research and Development Center for Efficient Utilization of Coastal Bioresources, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, PR China; Center for Ocean Mega-science, Chinese Academy of Sciences, Qingdao, Shandong, 266071, PR China.
| | - Jianmin Zhao
- Muping Coastal Environment Research Station, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, PR China; Research and Development Center for Efficient Utilization of Coastal Bioresources, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong, 264003, PR China; Center for Ocean Mega-science, Chinese Academy of Sciences, Qingdao, Shandong, 266071, PR China.
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Hepcidin gene silencing ameliorated inflammation and insulin resistance in adipose tissue of db/db mice via inhibiting METs formation. Mol Immunol 2021; 133:110-121. [PMID: 33640761 DOI: 10.1016/j.molimm.2021.02.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 02/02/2021] [Accepted: 02/14/2021] [Indexed: 12/11/2022]
Abstract
As a major feature of diabetes, inflammation is closely related to macrophage extracellular traps and the expression of hepcidin upregulated by diabetes is reportedly involved in chronic inflammation. Therefore, we aimed to explore whether hepcidin could be implicated in inflammation and macrophage extracellular traps (METs) formation. The diabetic db/db mouse model was established exhibiting insulin resistance (IR), inflammation, macrophages infiltration and higher expression of hepcidin, where samples were obtained from epididymal adipose tissue. We observed that inflammation and IR improved in adipose tissue of mice treated with hepcidin gene silencing. Furthermore, METs formation could be markedly inhibited via hepcidin gene silencing followed by attenuated inflammatory response due to METs, indicating hepcidin gene silencing played a key role in anti-inflammation by inhibiting METs formation. So, we concluded that hepcidin gene silencing has a potential for treatment of diabetes due to its ability to ameliorate inflammation via inhibiting METs formation.
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Okamato Y, Ghosh T, Okamoto T, Schuyler RP, Seifert J, Charry LL, Visser A, Feser M, Fleischer C, Pedrick C, August J, Moss L, Bemis EA, Norris JM, Kuhn KA, Demoruelle MK, Deane KD, Ghosh D, Holers VM, Hsieh EWY. Subjects at-risk for future development of rheumatoid arthritis demonstrate a PAD4-and TLR-dependent enhanced histone H3 citrullination and proinflammatory cytokine production in CD14 hi monocytes. J Autoimmun 2021; 117:102581. [PMID: 33310262 PMCID: PMC7855988 DOI: 10.1016/j.jaut.2020.102581] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022]
Abstract
The presence of anti-citrullinated protein/peptide antibodies (ACPA) and epitope spreading across the target autoantigens is a unique feature of rheumatoid arthritis (RA). ACPA are present in the peripheral blood for several years prior to the onset of arthritis and clinical classification of RA. ACPA recognize multiple citrullinated proteins, including histone H3 (H3). Intracellular citrullination of H3 in neutrophils and T cells is known to regulate immune cell function by promoting neutrophil extracellular trap formation and citrullinated autoantigen release as well as regulating the Th2/Th17 T cell phenotypic balance. However, the roles of H3 citrullination in other immune cells are not fully elucidated. We aimed to explore H3 citrullination and cytokine/metabolomic signatures in peripheral blood immune cells from subjects prior to and after the onset of RA, at baseline and in response to ex vivo toll-like receptor (TLR) stimulation. Here, we analyzed 13 ACPA (+) subjects without arthritis but at-risk for future development of RA, 14 early RA patients, and 13 healthy controls. We found significantly elevated H3 citrullination in CD14hi monocytes, as well as CD1c+ dendritic cells and CD66+ granulocytes. Unsupervised analysis identified two distinct subsets in CD14hi monocytes characterized by H3 modification and unique cytokine/metabolomic signatures. CD14hi monocytes with elevated TLR-stimulated H3 citrullination were significantly increased in ACPA (+) at-risk subjects. These cells were skewed to produce TNFα, MIP1β, IFNα, and partially IL-12. Additionally, they demonstrate peptidyl arginine deiminase 4 (PAD4) mediated upregulation of the glycolytic enzyme PFKFB3. These CD14hi monocytes with elevated H3 citrullination morphologically formed monocyte extracellular traps (METs). Taken together, dysregulated PAD4-driven cytokine production as well as MET formation in CD14hi monocytes in ACPA (+) at-risk subjects likely plays an important role in the development of RA via promoting and perpetuating inflammation and generation of citrullinated autoantigens.
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Affiliation(s)
- Yuko Okamato
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA; Tokyo Women's Medical University School of Medicine, Department of Rheumatology, Tokyo, Japan.
| | - Tusharkanti Ghosh
- Colorado School of Public Health, Department of Biostatistics and Informatics, Aurora, CO, USA
| | - Tsukasa Okamoto
- University of Colorado Denver, Department of Medicine, Aurora, CO, USA
| | - Ronald P Schuyler
- University of Colorado School of Medicine, Department of Immunology and Microbiology, Aurora, CO, USA
| | - Jennifer Seifert
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Laura Lenis Charry
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Ashley Visser
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Marie Feser
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Chelsie Fleischer
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Chong Pedrick
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Justin August
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Laurakay Moss
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Elizabeth A Bemis
- Colorado School of Public Health, Department of Epidemiology, Aurora, CO, USA
| | - Jill M Norris
- Colorado School of Public Health, Department of Epidemiology, Aurora, CO, USA
| | - Kristine A Kuhn
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | | | - Kevin D Deane
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Debashis Ghosh
- Colorado School of Public Health, Department of Biostatistics and Informatics, Aurora, CO, USA
| | - V Michael Holers
- University of Colorado Denver, Division of Rheumatology, Aurora, CO, USA
| | - Elena W Y Hsieh
- University of Colorado School of Medicine, Department of Immunology and Microbiology, Aurora, CO, USA; University of Colorado School of Medicine, Children's Hospital Colorado, Department of Pediatrics, Section of Allergy & Immunology, Aurora, CO, USA
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Gu T, Zhao S, Jin G, Song M, Zhi Y, Zhao R, Ma F, Zheng Y, Wang K, Liu H, Xin M, Han W, Li X, Dong CD, Liu K, Dong Z. Cytokine Signature Induced by SARS-CoV-2 Spike Protein in a Mouse Model. Front Immunol 2021; 11:621441. [PMID: 33584719 PMCID: PMC7876321 DOI: 10.3389/fimmu.2020.621441] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
Although COVID-19 has become a major challenge to global health, there are currently no efficacious agents for effective treatment. Cytokine storm syndrome (CSS) can lead to acute respiratory distress syndrome (ARDS), which contributes to most COVID-19 mortalities. Research points to interleukin 6 (IL-6) as a crucial signature of the cytokine storm, and the clinical use of the IL-6 inhibitor tocilizumab shows potential for treatment of COVID-19 patient. In this study, we challenged wild-type and adenovirus-5/human angiotensin-converting enzyme 2-expressing BALB/c mice with a combination of polyinosinic-polycytidylic acid and recombinant SARS-CoV-2 spike-extracellular domain protein. High levels of TNF-α and nearly 100 times increased IL-6 were detected at 6 h, but disappeared by 24 h in bronchoalveolar lavage fluid (BALF) following immunostimulant challenge. Lung injury observed by histopathologic changes and magnetic resonance imaging at 24 h indicated that increased TNF-α and IL-6 may initiate CSS in the lung, resulting in the continual production of inflammatory cytokines. We hypothesize that TNF-α and IL-6 may contribute to the occurrence of CSS in COVID-19. We also investigated multiple monoclonal antibodies (mAbs) and inhibitors for neutralizing the pro-inflammatory phenotype of COVID-19: mAbs against IL-1α, IL-6, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and inhibitors of p38 and JAK partially relieved CSS; mAbs against IL-6, TNF-α, and GM-CSF, and inhibitors of p38, extracellular signal-regulated kinase, and myeloperoxidase somewhat reduced neutrophilic alveolitis in the lung. This novel murine model opens a biologically safe, time-saving avenue for clarifying the mechanism of CSS/ARDS in COVID-19 and developing new therapeutic drugs.
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Affiliation(s)
- Tingxuan Gu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Simin Zhao
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
- Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Guoguo Jin
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
- The Henan Luoyang Orthopedic Hospital, Zhengzhou, China
| | - Mengqiu Song
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Yafei Zhi
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Ran Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Fayang Ma
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Yaqiu Zheng
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Keke Wang
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Hui Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Mingxia Xin
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Wei Han
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Xiang Li
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China
| | | | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
- Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
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Kloc M, Uosef A, Kubiak JZ, Ghobrial RM. Macrophage Proinflammatory Responses to Microorganisms and Transplanted Organs. Int J Mol Sci 2020; 21:ijms21249669. [PMID: 33352942 PMCID: PMC7766629 DOI: 10.3390/ijms21249669] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/09/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023] Open
Abstract
Tissue-resident macrophages and those conscripted from the blood/bone marrow are professional phagocytes. They play a role in tissue homeostasis, replacement, and healing, and are the first-line responders to microbial (viral, bacterial, and fungi) infections. Intrinsic ameboid-type motility allows non-resident macrophages to move to the site of inflammation or injury, where, in response to the inflammatory milieu they perform the anti-microbial and/or tissue repair functions. Depending on the need and the signaling from the surrounding tissue and other immune cells, macrophages acquire morphologically and functionally different phenotypes, which allow them to play either pro-inflammatory or anti-inflammatory functions. As such, the macrophages are also the major players in the rejection of the transplanted organs making an excellent target for the novel anti-rejection therapies in clinical transplantation. In this review, we describe some of the less covered aspects of macrophage response to microbial infection and organ transplantation.
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Affiliation(s)
- Malgorzata Kloc
- The Houston Methodist Research Institute, Houston, TX 77030, USA; (A.U.); (R.M.G.)
- Department of Surgery, The Houston Methodist Hospital, Houston, TX 77030, USA
- MD Anderson Cancer Center, Department of Genetics Houston, The University of Texas, Austin, TX 77030, USA
- Correspondence:
| | - Ahmed Uosef
- The Houston Methodist Research Institute, Houston, TX 77030, USA; (A.U.); (R.M.G.)
- Department of Surgery, The Houston Methodist Hospital, Houston, TX 77030, USA
| | - Jacek Z. Kubiak
- Laboratory of Regenerative Medicine and Cell Biology, Military Institute of Hygiene and Epidemiology (WIHE), 01-163 Warsaw, Poland;
- Cell Cycle Group, Faculty of Medicine, Institute of Genetics and Development of Rennes (IGDR), University Rennes, UMR 6290, CNRS, 35043 Rennes, France
| | - Rafik M. Ghobrial
- The Houston Methodist Research Institute, Houston, TX 77030, USA; (A.U.); (R.M.G.)
- Department of Surgery, The Houston Methodist Hospital, Houston, TX 77030, USA
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Morris G, Bortolasci CC, Puri BK, Olive L, Marx W, O'Neil A, Athan E, Carvalho AF, Maes M, Walder K, Berk M. The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach. Life Sci 2020; 258:118166. [PMID: 32739471 PMCID: PMC7392886 DOI: 10.1016/j.lfs.2020.118166] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/23/2020] [Accepted: 07/25/2020] [Indexed: 01/10/2023]
Abstract
In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.
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Affiliation(s)
- Gerwyn Morris
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Chiara C. Bortolasci
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia,Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia,Corresponding author at: IMPACT – the Institute for Mental and Physical Health and Clinical Translation, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria 3218, Australia
| | | | - Lisa Olive
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia,School of Psychology, Deakin University, Geelong, Australia
| | - Wolfgang Marx
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Adrienne O'Neil
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia,Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
| | - Eugene Athan
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia,Barwon Health, Geelong, Australia
| | - Andre F. Carvalho
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia,Department of Psychiatry, University of Toronto, Toronto, Canada,Centre for Addiction and Mental Health (CAMH), Toronto, Canada
| | - Michael Maes
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia,Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand,Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
| | - Ken Walder
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia,Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia
| | - Michael Berk
- Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia,Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia
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48
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Martin-Sanchez D, Fontecha-Barriuso M, Martinez-Moreno JM, Ramos AM, Sanchez-Niño MD, Guerrero-Hue M, Moreno JA, Ortiz A, Sanz AB. Ferroptosis and kidney disease. Nefrologia 2020; 40:384-394. [PMID: 32624210 DOI: 10.1016/j.nefro.2020.03.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 03/04/2020] [Indexed: 02/08/2023] Open
Abstract
Cell death is a finely regulated process occurring through different pathways. Regulated cell death, either through apoptosis or regulated necrosis offers the possibility of therapeutic intervention. Necroptosis and ferroptosis are among the best studied forms of regulated necrosis in the context of kidney disease. We now review the current evidence supporting a role for ferroptosis in kidney disease and the implications of this knowledge for the design of novel therapeutic strategies. Ferroptosis is defined functionally, as a cell modality characterized by peroxidation of certain lipids, constitutively suppressed by GPX4 and inhibited by iron chelators and lipophilic antioxidants. There is functional evidence of the involvement of ferroptosis in diverse forms of kidneys disease. In a well characterized nephrotoxic acute kidney injury model, ferroptosis caused an initial wave of death, triggering an inflammatory response that in turn promoted necroptotic cell death that perpetuated kidney dysfunction. This suggests that ferroptosis inhibitors may be explored as prophylactic agents in clinical nephrotoxicity or ischemia-reperfusion injury such as during kidney transplantation. Transplantation offers the unique opportunity of using anti-ferroptosis agent ex vivo, thus avoiding bioavailability and in vivo pharmacokinetics and pharmacodynamics issues.
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Affiliation(s)
- Diego Martin-Sanchez
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; REDINREN, Madrid, Spain
| | - Miguel Fontecha-Barriuso
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; REDINREN, Madrid, Spain
| | - Julio M Martinez-Moreno
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; REDINREN, Madrid, Spain
| | - Adrian M Ramos
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; REDINREN, Madrid, Spain
| | - Maria D Sanchez-Niño
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; REDINREN, Madrid, Spain
| | | | - Juan A Moreno
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, Spain; Hospital Universitario Reina Sofia, Cordoba, Spain; Centre of Biomedical Research in Network of Cardiovascular Disease (CIBERCV), Madrid, Spain
| | - Alberto Ortiz
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; REDINREN, Madrid, Spain; School of Medicine, UAM, Madrid, Spain
| | - Ana B Sanz
- Research Institute-Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain; REDINREN, Madrid, Spain.
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49
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Abstract
There is abundant evidence that infectious sepsis both in humans and mice with polymicrobial sepsis results in robust activation of complement. Major complement activation products involved in sepsis include C5a anaphylatoxin and its receptors (C5aR1 and C5aR2) and, perhaps, the terminal complement activation product, C5b-9. These products (and others) also cause dysfunction of the innate immune system, with exaggerated early proinflammatory responses, followed by decline of the innate immune system, leading to immunosuppression and multiorgan dysfunction. Generation of C5a during sepsis also leads to activation of neutrophils and macrophages and ultimate appearance of extracellular histones, which have powerful proinflammatory and prothrombotic activities. The distal complement activation product, C5b-9, triggers intracellular Ca fluxes in epithelial and endothelial cells. Histones activate the NLRP3 inflammasome, products of which can damage cells. C5a also activates MAPKs and Akt signaling pathways in cardiomyocytes, causing buildup of [Ca]i, defective action potentials and substantial cell dysfunction, resulting in cardiac and other organ dysfunction. Cardiac dysfunction can be quantitated by ECHO-Doppler parameters. In vivo interventions that block these complement-dependent products responsible for organ dysfunction in sepsis reduce the intensity of sepsis. The obvious targets in sepsis are C5a and its receptors, histones, and perhaps the MAPK pathways. Blockade of C5 has been considered in sepsis, but the FDA-approved antibody (eculizumab) is known to compromise defenses against neisseria and pneumonococcal bacteria, and requires immunization before the mAb to C5 can be used clinically. Small molecular blocking agents for C5aRs are currently in development and may be therapeutically effective for treatment of sepsis.
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Gusev EY, Zotova NV. Cellular Stress and General Pathological Processes. Curr Pharm Des 2020; 25:251-297. [PMID: 31198111 DOI: 10.2174/1381612825666190319114641] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 03/13/2019] [Indexed: 02/06/2023]
Abstract
From the viewpoint of the general pathology, most of the human diseases are associated with a limited number of pathogenic processes such as inflammation, tumor growth, thrombosis, necrosis, fibrosis, atrophy, pathological hypertrophy, dysplasia and metaplasia. The phenomenon of chronic low-grade inflammation could be attributed to non-classical forms of inflammation, which include many neurodegenerative processes, pathological variants of insulin resistance, atherosclerosis, and other manifestations of the endothelial dysfunction. Individual and universal manifestations of cellular stress could be considered as a basic element of all these pathologies, which has both physiological and pathophysiological significance. The review examines the causes, main phenomena, developmental directions and outcomes of cellular stress using a phylogenetically conservative set of genes and their activation pathways, as well as tissue stress and its role in inflammatory and para-inflammatory processes. The main ways towards the realization of cellular stress and its functional blocks were outlined. The main stages of tissue stress and the classification of its typical manifestations, as well as its participation in the development of the classical and non-classical variants of the inflammatory process, were also described. The mechanisms of cellular and tissue stress are structured into the complex systems, which include networks that enable the exchange of information with multidirectional signaling pathways which together make these systems internally contradictory, and the result of their effects is often unpredictable. However, the possible solutions require new theoretical and methodological approaches, one of which includes the transition to integral criteria, which plausibly reflect the holistic image of these processes.
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Affiliation(s)
- Eugeny Yu Gusev
- Laboratory of the Immunology of Inflammation, Institute of Immunology and Physiology, Yekaterinburg, Russian Federation
| | - Natalia V Zotova
- Laboratory of the Immunology of Inflammation, Institute of Immunology and Physiology, Yekaterinburg, Russian Federation.,Department of Medical Biochemistry and Biophysics, Ural Federal University named after B.N.Yeltsin, Yekaterinburg, Russian Federation
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