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

Nat Genet. 2014 Oct;46(10):1140-6. doi: 10.1038/ng.3089.

Scott W Canna ¹, Adriana A de Jesus ², Sushanth Gouni ¹, Stephen R Brooks ³, Bernadette Marrero ², Yin Liu ², Michael A DiMattia ⁴, Kristien J M Zaal ⁵, Gina A Montealegre Sanchez ⁶, Hanna Kim ², Dawn Chapelle ⁶, Nicole Plass ⁶, Yan Huang ², Alejandro V Villarino ¹, Angelique Biancotto ⁷, Thomas A Fleisher ⁸, Joseph A Duncan ⁹, John J O'Shea ¹, Susanne Benseler ¹⁰, Alexei Grom ¹¹, Zuoming Deng ³, Ronald M Laxer ¹², Raphaela Goldbach-Mansky ²

Affiliations

1 Molecular Immunology and Inflammation Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
2 Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
3 Biodata Mining and Discovery Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
4 Laboratory of Structural Biology, NIAMS, NIH, Bethesda, Maryland, USA.
5 Light Imaging Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
6 1] Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA. [2] Office of the Clinical Director, NIAMS, NIH, Bethesda, Maryland, USA.
7 Center for Human Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
8 Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Maryland, USA.
9 Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
10 Pediatric Rheumatology, Alberta Children's Hospital and University of Calgary, Calgary, Alberta, Canada.
11 Pediatric Rheumatology, Cincinnati Children's Hospital and University of Cincinnati, Cincinnati, Ohio, USA.
12 Pediatric Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada.

PMID: 25217959 DOI: 10.1038/ng.3089

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.

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