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- Title
An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
- Authors
Canna, Scott W; Gouni, Sushanth; Villarino, Alejandro V; O'Shea, John J; Benseler, Susanne; Grom, Alexei; Laxer, Ronald M; de Jesus, Adriana A; Marrero, Bernadette; Liu, Yin; Kim, Hanna; Huang, Yan; Goldbach-Mansky, Raphaela; Brooks, Stephen R; Deng, Zuoming; DiMattia, Michael A; Zaal, Kristien J M; Sanchez, Gina A Montealegre; Chapelle, Dawn; Plass, Nicole
- Abstract
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, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.
- Subjects
INFLAMMATION; MACROPHAGE activation syndrome; PATHOGENIC microorganisms; INTERLEUKINS; CRYOPYRIN-associated periodic syndromes; MISSENSE mutation
- Publication
Nature Genetics, 2014, Vol 46, Issue 10, p1140
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.3089