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      The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases

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          Abstract

          The activation of the pyrin inflammasome represents a highly intriguing mechanism employed by the innate immune system to effectively counteract pathogenic agents. Despite its key role in innate immunity, pyrin has also garnered significant attention due to its association with a range of autoinflammatory diseases (AIDs) including familial Mediterranean fever caused by disruption of the MEFV gene, or in other genes involved in its complex regulation mechanisms. Pyrin activation is strictly dependent on homeostasis-altering molecular processes, mostly consisting of the disruption of the small Ras Homolog Family Member A (RhoA) GTPases by pathogen toxins. The downstream pathways are regulated by the phosphorylation of specific pyrin residues by the kinases PKN1/2 and the binding of the chaperone 14-3-3. Furthermore, a key role in pyrin activation is played by the cytoskeleton and gasdermin D, which is responsible for membrane pores in the context of pyroptosis. In addition, recent evidence has highlighted the role of steroid hormone catabolites and alarmins S100A8/A9 and S100A12 in pyrin-dependent inflammation. The aim of this article is to offer a comprehensive overview of the most recent evidence on the pyrin inflammasome and its molecular pathways to better understand the pathogenesis behind the significant group of pyrin-related AIDs.

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          Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.

          Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.
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            Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.

            Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1β processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1β secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.
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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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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2197016Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1919803Role: Role: Role:
                Role: Role: Role:
                URI : https://loop.frontiersin.org/people/1938793Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/363769Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/24505Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/24775Role: Role: Role: Role:
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                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                05 January 2024
                2023
                : 14
                : 1341680
                Affiliations
                [1] 1 Department of Pediatrics, "G. D'Annunzio" University of Chieti , Chieti, Italy
                [2] 2 Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine , Ankara, Türkiye
                [3] 3 UOC Rheumatology and Autoinflammatory Diseases, IRCCS Istituto Giannina Gaslini , Genova, Italy
                Author notes

                Edited by: Ozgur Kasapcopur, Istanbul University-Cerrahpasa, Türkiye

                Reviewed by: Sezgin Sahin, Istanbul University-Cerrahpasa, Türkiye

                Yuya Fujita, Fukushima Medical University School of Medicine, Japan

                *Correspondence: Saverio La Bella, saveriolabella@ 123456outlook.it
                Article
                10.3389/fimmu.2023.1341680
                10796709
                38250061
                5c8e8a85-3ec8-4908-937e-c5fab5f01baa
                Copyright © 2024 La Bella, Di Ludovico, Di Donato, Basaran, Ozen, Gattorno, Chiarelli and Breda

                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
                : 20 November 2023
                : 14 December 2023
                Page count
                Figures: 3, Tables: 5, Equations: 0, References: 151, Pages: 18, Words: 9662
                Funding
                The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
                Categories
                Immunology
                Review
                Custom metadata
                Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders

                Immunology
                pyrin,inflammasome,familial mediterranean fever,fmf,autoinflammatory diseases,il-1,gasdermin d
                Immunology
                pyrin, inflammasome, familial mediterranean fever, fmf, autoinflammatory diseases, il-1, gasdermin d

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