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      The NLRP3 and Pyrin Inflammasomes: Implications in the Pathophysiology of Autoinflammatory Diseases

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          Abstract

          Inflammasomes are multiprotein complexes that critically control different aspects of innate and adaptive immunity. Among them we could highlight the release of pro-inflammatory cytokines that induce and maintain the inflammatory response. Usually, inflammasomes result from oligomerization of a nucleotide-binding domain-like receptor (NLR) after sensing different pathogenic or endogenous sterile dangerous signals; however, other proteins such as absent in melanoma 2, retinoic acid-inducible gene I, or pyrin could also form inflammasome platforms. Inflammasome oligomerization leads to caspase-1 activation and the processing and release of the pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18. Mutations in different inflammasomes are causative for multiple periodic hereditary syndromes or autoinflammatory diseases, characterized by acute systemic inflammatory flares not associated with infections, tumors, or autoimmunity. This review focuses on germline mutations that have been described in cryopyrin-associated periodic syndrome (CAPS) for NLRP3 or in familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) for MEFV. Besides the implication of inflammasomes in autoinflammatory syndromes, these molecular platforms are involved in the pathophysiology of different illnesses, including chronic inflammatory diseases, degenerative processes, fibrosis, or metabolic diseases. Therefore, drug development targeting inflammasome activation is a promising field in expansion.

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          Most cited references108

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          Origin and physiological roles of inflammation.

          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus.

            Inflammasomes are large cytoplasmic complexes that sense microbial infections/danger molecules and induce caspase-1 activation-dependent cytokine production and macrophage inflammatory death. The inflammasome assembled by the NOD-like receptor (NLR) protein NLRC4 responds to bacterial flagellin and a conserved type III secretion system (TTSS) rod component. How the NLRC4 inflammasome detects the two bacterial products and the molecular mechanism of NLRC4 inflammasome activation are not understood. Here we show that NAIP5, a BIR-domain NLR protein required for Legionella pneumophila replication in mouse macrophages, is a universal component of the flagellin-NLRC4 pathway. NAIP5 directly and specifically interacted with flagellin, which determined the inflammasome-stimulation activities of different bacterial flagellins. NAIP5 engagement by flagellin promoted a physical NAIP5-NLRC4 association, rendering full reconstitution of a flagellin-responsive NLRC4 inflammasome in non-macrophage cells. The related NAIP2 functioned analogously to NAIP5, serving as a specific inflammasome receptor for TTSS rod proteins such as Salmonella PrgJ and Burkholderia BsaK. Genetic analysis of Chromobacterium violaceum infection revealed that the TTSS needle protein CprI can stimulate NLRC4 inflammasome activation in human macrophages. Similarly, CprI is specifically recognized by human NAIP, the sole NAIP family member in human. The finding that NAIP proteins are inflammasome receptors for bacterial flagellin and TTSS apparatus components further predicts that the remaining NAIP family members may recognize other unidentified microbial products to activate NLRC4 inflammasome-mediated innate immunity. © 2011 Macmillan Publishers Limited. All rights reserved
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              Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.

              Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted "postbiotic" metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/353117
                URI : http://frontiersin.org/people/u/24396
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                27 January 2017
                2017
                : 8
                : 43
                Affiliations
                [1] 1Unidad de Inflamación Molecular, Instituto Murciano de Investigación Biosanitaria-Virgen de la Arrixaca (IMIB-Arrixaca), CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca , Murcia, Spain
                [2] 2Unidad de Reumatología Pediátrica, Hospital Clínico Universitario Virgen de la Arrixaca , Murcia, Spain
                Author notes

                Edited by: José Hernández-Rodríguez, Hospital Clinic of Barcelona, Spain

                Reviewed by: Manel Juan, Hospital Clinic of Barcelona, Spain; Dominic De Nardo, Walter and Eliza Hall Institute of Medical Research, Australia

                *Correspondence: Pablo Pelegrín, pablo.pelegrin@ 123456ffis.es

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.00043
                5271383
                28191008
                b8f0aa4c-0f7a-4316-aba4-5d18e05ba628
                Copyright © 2017 de Torre-Minguela, Mesa del Castillo and Pelegrín.

                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) or licensor 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
                : 01 December 2016
                : 11 January 2017
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 204, Pages: 17, Words: 13944
                Funding
                Funded by: European Research Council 10.13039/501100000781
                Award ID: ERC-2013-CoG 614578
                Funded by: Instituto de Salud Carlos III 10.13039/501100004587
                Award ID: PI13/00174
                Categories
                Immunology
                Review

                Immunology
                inflammation,nlrp3,pyrin,extracellular atp,p2x7 receptor,cryopyrin-associated periodic syndrome,familial mediterranean fever

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