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      ENaC-mediated sodium influx exacerbates NLRP3-dependent inflammation in cystic fibrosis

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          Abstract

          Cystic Fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR-mediated chloride and bicarbonate transport, with dysregulation of epithelial sodium channels (ENaC). These changes alter fluid and electrolyte homeostasis and result in an exaggerated proinflammatory response driven, in part, by infection. We tested the hypothesis that NLRP3 inflammasome activation and ENaC upregulation drives exaggerated innate-immune responses in this multisystem disease. We identify an enhanced proinflammatory signature, as evidenced by increased levels of IL-18, IL-1β, caspase-1 activity and ASC-speck release in monocytes, epithelia and serum with CF-associated mutations; these differences were reversed by pretreatment with NLRP3 inflammasome inhibitors and notably, inhibition of amiloride-sensitive sodium (Na +) channels. Overexpression of β-ENaC, in the absence of CFTR dysfunction, increased NLRP3-mediated inflammation, indicating that dysregulated, ENaC-dependent signalling may drive exaggerated inflammatory responses in CF. These data support a role for sodium in modulating NLRP3 inflammasome activation.

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          Most cited references55

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          The NLRP3 inflammasome: molecular activation and regulation to therapeutics

          NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase-1-dependent release of the proinflammatory cytokines, IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical basis of NLRP3 activation and regulation, and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.
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            Pro-inflammatory programmed cell death.

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              An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.

              Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.) 2009 Massachusetts Medical Society
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                18 September 2019
                2019
                : 8
                : e49248
                Affiliations
                [1 ]deptLeeds Institute of Rheumatic and Musculoskeletal Medicine University of Leeds LeedsUnited Kingdom
                [2 ]deptLeeds Institute of Medical Research University of Leeds LeedsUnited Kingdom
                [3 ]deptLeeds Cystic Fibrosis Trust Strategic Research Centre University of Leeds LeedsUnited Kingdom
                [4 ]deptDepartment of Biochemistry University of Lausanne LausanneSwitzerland
                [5 ]deptDepartment of Clinical Immunology and Allergy St James’s University Hospital LeedsUnited Kingdom
                [6 ]deptAdult Cystic Fibrosis Unit St James’ University Hospital LeedsUnited Kingdom
                Radboud University Medical Centre Netherlands
                Indian Institute of Science Education and Research (IISER) India
                Radboud University Medical Centre Netherlands
                Radboud University Medical Centre Netherlands
                Radboud University Netherlands
                Author notes
                [†]

                These authors contributed equally to this work.

                [‡]

                These authors also contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-2468-0218
                https://orcid.org/0000-0001-5154-4815
                https://orcid.org/0000-0002-9986-5279
                https://orcid.org/0000-0003-2108-1615
                http://orcid.org/0000-0002-6969-822X
                http://orcid.org/0000-0001-7910-0554
                https://orcid.org/0000-0001-7723-1868
                https://orcid.org/0000-0002-1015-0745
                Article
                49248
                10.7554/eLife.49248
                6764826
                31532390
                28673120-88bd-4eee-b8bb-a5c661147cc0
                © 2019, Scambler et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 11 June 2019
                : 17 September 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000292, Cystic Fibrosis Trust;
                Award ID: SRC009
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000777, University of Leeds;
                Award ID: 110 University Scholarship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003141, Consejo Nacional de Ciencia y Tecnología;
                Award ID: CONACyT
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Human Biology and Medicine
                Immunology and Inflammation
                Custom metadata
                Dysfunction and overexpression of ENaC-mediated sodium influx exacerbates activation of NLRP3-inflammasome mediated inflammation in cells with CF-associated mutations and is modulated by inhibition of these amiloride-sensitive sodium (Na +) channels.

                Life sciences
                inflammasome,cystic fibrosis,sodium transport,potassium transport,autoinflammation,nlrp3,human

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