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      Inflammasomes: Pandora’s box for sepsis

      1 , 2

      Journal of Inflammation Research

      Dove Medical Press

      inflammasomes, sepsis, cytokines, inflammation, pathogens

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          Abstract

          Sepsis was known to ancient Greeks since the time of great physician Hippocrates (460–377 BC) without exact information regarding its pathogenesis. With time and medical advances, it is now considered as a condition associated with organ dysfunction occurring in the presence of systemic infection as a result of dysregulation of the immune response. Still with this advancement, we are struggling for the development of target-based therapeutic approach for the management of sepsis. The advancement in understanding the immune system and its working has led to novel discoveries in the last 50 years, including different pattern recognition receptors. Inflammasomes are also part of these novel discoveries in the field of immunology which are <20 years old in terms of their first identification. They serve as important cytosolic pattern recognition receptors required for recognizing cytosolic pathogens, and their pathogen-associated molecular patterns play an important role in the pathogenesis of sepsis. The activation of both canonical and non-canonical inflammasome signaling pathways is involved in mounting a proinflammatory immune response via regulating the generation of IL-1β, IL-18, IL-33 cytokines and pyroptosis. In addition to pathogens and their pathogen-associated molecular patterns, death/damage-associated molecular patterns and other proinflammatory molecules involved in the pathogenesis of sepsis affect inflammasomes and vice versa. Thus, the present review is mainly focused on the inflammasomes, their role in the regulation of immune response associated with sepsis, and their targeting as a novel therapeutic approach.

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          Most cited references 288

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          Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.

          Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.
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            The inflammasomes: guardians of the body.

            The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1beta and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.
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              H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase.

              Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention. Here we show that H2S is physiologically generated by cystathionine gamma-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation. These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure.
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                Author and article information

                Journal
                J Inflamm Res
                J Inflamm Res
                Journal of Inflammation Research
                Journal of Inflammation Research
                Dove Medical Press
                1178-7031
                2018
                11 December 2018
                : 11
                : 477-502
                Affiliations
                [1 ]Children’s Health Queensland Clinical Unit, School of Clinical Medicine, Faculty of Medicine, Mater Research, University of Queensland, Brisbane, Australia, vij_tox@ 123456yahoo.com
                [2 ]School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia, vij_tox@ 123456yahoo.com
                Author notes
                Correspondence: Vijay Kumar, Children’s Health Queensland Clinical Unit, Faculty of Medicine, Mater Research, University of Queensland, Skerman Building (65), St Lucia, Brisbane, Queensland 4078, Australia, Email vij_tox@ 123456yahoo.com
                Article
                jir-11-477
                10.2147/JIR.S178084
                6294171
                © 2018 Kumar. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Immunology

                pathogens, inflammation, cytokines, sepsis, inflammasomes

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