Unknown,Transcriptomics,Genomics,Proteomics

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An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

ABSTRACT: Inflammasomes are intracellular innate immune sensors that respond to pathogen and damage-associated signals with the proteolytic cleavage of caspase-1, resulting in IL-1_ and IL-18 secretion and macrophage pyroptosis. The discovery that heterozygous gain-of-function mutations in NLRP3 lead to oversecretion of IL-1_ and cause the autoinflammatory disease spectrum Cryopyrin Associated Periodic Syndrome (CAPS), led to the successful use of IL-1 blocking therapies1. We found that a de novo missense mutation in the regulatory domain of the NLRC4 (IPAF, CARD12) inflammasome causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous production of the inflammasome-dependent cytokines IL-1Â² and IL-18 exceeding levels in CAPS patients. The NLRC4 mutation led to constitutive caspase-1 cleavage in transduced cells and enhanced spontaneous production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the autoinflammatory paradigm to include MAS and suggests novel targets for therapy. Whole blood RNA-seq from seven timepoints of one patient with NLRC4-MAS as compared to five healthy pediatric controls, 7 NOMID patients with active disease prior to anakinra treatment and the same 7 NOMID patients with inactive disease after anakinra treatment. Please note that seven time points are chronologic time point. They are ordinal, in that "1" was drawn before "2", but the distance in time between points is not constant. Thus, time points 4 through 7 correspond to samples drawn while the patient was well AND on treatment. However there may be differences between 4 and 7 pertaining to the length of treatment, and for that reason any of these samples were not considered replicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Scott Canna

PROVIDER: E-GEOD-57253 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.

Canna Scott W SW de Jesus Adriana A AA Gouni Sushanth S Brooks Stephen R SR Marrero Bernadette B Liu Yin Y DiMattia Michael A MA Zaal Kristien J M KJ Sanchez Gina A Montealegre GA Kim Hanna H Chapelle Dawn D Plass Nicole N Huang Yan Y Villarino Alejandro V AV Biancotto Angelique A Fleisher Thomas A TA Duncan Joseph A JA O'Shea John J JJ Benseler Susanne S Grom Alexei A Deng Zuoming Z Laxer Ronald M RM Goldbach-Mansky Raphaela R

Nature genetics 20140914 10

Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, en ...[more]

PMID: 25217959

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Project description:BACKGROUND: Cryopyrin-Associated Periodic Syndrome (CAPS) is an autoinflammatory condition consequence of monoallelic variants in the NLRP3 gene that exacerbate IL-1β production. These variants are gain-of-function, but the exact regulatory mechanism of the NLRP3 CAPS-inflammasome is not well yet understood. It is considered as a hypersensitive inflammasome triggered by cell priming, but patients with CAPS and animal disease models present inflammatory flares in the absence of external triggers.OBJECTIVES: To study the regulation and activation of the NLRP3 inflammasome in CAPS.METHODS: CAPS derived blood samples and genetically modified macrophages expressing different NLRP3 CAPS-associated variants were used to assess NLRP3 function dissociated from cell priming and cell metabolism.RESULTS: We found that CAPS-associated variants constitutively result in active NLRP3 inflammasomes, that induce a basal cleavage of gasdermin D, IL-18 release and pyroptosis. The constitutive active NLRP3 inflammasome was blocked by MCC950 and was dependent on NLRP3 expression level, being further regulated by deubiquitination. We also showed that activation of NF-κB with lipopolysaccharide or other endogenous host-derived molecules (palmitate, S100A9 or IL-6) further modulated the activation of the NLRP3 CAPS inflammasome and expanded the repertoire of molecules secreted from CAPS macrophages to IL-1β, IL-1α, HMGB1, cystatin B and the P2X7 receptor, identifying novel proteins involved in CAPS pathogenesis. NLRP3 inflammasomes with CAPS associated variants affected the immunometabolism of the myeloid compartment and impaired glycolysis.CONCLUSIONS: These findings demonstrate that NLRP3 CAPS-associated variants form a constitutive active inflammasome that induce basal pyroptosis and IL-18 release without cell priming, suggesting a priming-independent mechanism for the initiation of CAPS flares characterized with a profound affection in the immunometabolism.

Project description:The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in the CIAS1 gene that result in increased production and secretion of active IL-1≤. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bony growth plates, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n=14) before treatment [lesional (LS) and non-lesional (pre-NL) skin] and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®), to normal skin (n=5). Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c+ dermal dendritic cells and CD163+ macrophages expressed activated caspase-1 and are the likely sources of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3+ T cells and HLA-DR+ cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. Differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification are indicative of epigenetic modification in the various tissue states. Overall, the dysregulated genes and pathways suggest extensive “adaptive” mechanisms to control inflammation, and maintain tissue homeostasis in the skin of patients with NOMID. To determine the transcsriptome of skin samples in Neonatal-onset Multisystem Inflammatory Disease (NOMID), using pre-treatment non-lesional (pre-NL, n=4); lesional (LS, n=6); post-treatment non-lesional (post-NL, n=8), and normal skin (n=5). Comparison of mean gene expression of each group at baseline, and considering treatment effect

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An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

Publications

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.

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