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      Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review

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          Abstract

          Extracellular histones are crucial damage-associated molecular patterns involved in the development and progression of multiple critical and inflammatory diseases, such as sepsis, pancreatitis, trauma, acute liver failure, acute respiratory distress syndrome, vasculitis and arthritis. During the past decade, the physiopathologic mechanisms of histone-mediated hyperinflammation, endothelial dysfunction, coagulation activation, neuroimmune injury and organ dysfunction in diseases have been systematically elucidated. Emerging preclinical evidence further shows that anti-histone strategies with either their neutralizers (heparin, heparinoids, nature plasma proteins, small anion molecules and nanomedicines, etc.) or extracorporeal blood purification techniques can significantly alleviate histone-induced deleterious effects, and thus improve the outcomes of histone-related critical and inflammatory animal models. However, a systemic evaluation of the efficacy and safety of these histone-targeting therapeutic strategies is currently lacking. In this review, we first update our latest understanding of the underlying molecular mechanisms of histone-induced hyperinflammation, endothelial dysfunction, coagulopathy, and organ dysfunction. Then, we summarize the latest advances in histone-targeting therapy strategies with heparin, anti-histone antibodies, histone-binding proteins or molecules, and histone-affinity hemoadsorption in pre-clinical studies. Finally, challenges and future perspectives for improving the clinical translation of histone-targeting therapeutic strategies are also discussed to promote better management of patients with histone-related diseases.

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          Neutrophil extracellular traps in immunity and disease

          Neutrophils are innate immune phagocytes that have a central role in immune defence. Our understanding of the role of neutrophils in pathogen clearance, immune regulation and disease pathology has advanced dramatically in recent years. Web-like chromatin structures known as neutrophil extracellular traps (NETs) have been at the forefront of this renewed interest in neutrophil biology. The identification of molecules that modulate the release of NETs has helped to refine our view of the role of NETs in immune protection, inflammatory and autoimmune diseases and cancer. Here, I discuss the key findings and concepts that have thus far shaped the field of NET biology.
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            The inflammasomes.

            Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. 2010 Elsevier Inc. All rights reserved.
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              Neutrophil extracellular traps in COVID-19

              In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have the potential to propagate inflammation and microvascular thrombosis — including in the lungs of patients with acute respiratory distress syndrome. We now report that sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3); the latter 2 are specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute-phase reactants, including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19. Serum levels of neutrophil extracellular traps identify COVID-19 patients with more severe respiratory disease.
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                Author and article information

                Contributors
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                URI : https://loop.frontiersin.org/people/813508Role:
                URI : https://loop.frontiersin.org/people/1772503Role:
                Role: Role:
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                URI : https://loop.frontiersin.org/people/1185653Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1149858Role: Role: Role: Role: Role:
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                14 August 2024
                2024
                : 15
                : 1438984
                Affiliations
                [1] 1 Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University , Chengdu, China
                [2] 2 State Key Laboratory of Polymer Materials Engineering, College of Polymer Science and Engineering, Sichuan University , Chengdu, China
                [3] 3 Department of Rheumatology and Immunology, West China Hospital of Sichuan University , Chengdu, China
                [4] 4 Jiujiang City Key Laboratory of Cell Therapy, Department of Nephrology, Jiujiang No. 1 People’s Hospital , Jiujiang, China
                [5] 5 Med+ Biomaterial Institute of West China Hospital/West China School of Medicine, Sichuan University , Chengdu, China
                [6] 6 Med-X Center for Materials, Sichuan University , Chengdu, China
                Author notes

                Edited by: Alexander Brill, University of Birmingham, United Kingdom

                Reviewed by: Andrew Weber, Northwell Health, United States

                Jose Luis García-Giménez, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain

                Indranil Biswas, Oklahoma Medical Research Foundation, United States

                *Correspondence: Baihai Su, subaihai@ 123456scu.edu.cn ; Yupei Li, liyupei123@ 123456wchscu.cn
                Article
                10.3389/fimmu.2024.1438984
                11349558
                39206200
                f4734532-9fce-474e-8659-516ca6e95de0
                Copyright © 2024 Yang, Peng, Zhang, Chen, Liu, Jiang, Jin, Han, Su and Li

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 May 2024
                : 29 July 2024
                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 216, Pages: 22, Words: 11558
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82300848, U21A2098
                Funded by: Sichuan Province Science and Technology Support Program , doi 10.13039/100012542;
                Award ID: 23NSFSC4038, 22NSFSC3208
                Funded by: Natural Science Foundation of Jiangxi Province , doi 10.13039/501100004479;
                Award ID: 20232BAB206031
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. We acknowledge that this work is financially sponsored by the National Science Foundation of China (Grant No. 82300848 and U21A2098), the Sichuan Science and Technology Program (Grant No. 23NSFSC4038 and 22NSFSC3208), the Jiangxi Provincial Natural Science Foundation (Grant No. 20232BAB206031) and the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University (Grant No. ZYJC21010) and the Post-Doctor Research Project of West China Hospital, Sichuan University (Grant No. 2021HXBH084).
                Categories
                Immunology
                Review
                Custom metadata
                Inflammation

                Immunology
                extracellular histones,damage-associated molecular patterns,inflammation,histone-neutralization,heparin,blood purification

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