GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever
Year: 2018
Type: article
Abstract: Pyroptosis is an inflammasome-induced lytic cell death mode, the physiological role of which in chronic inflammatory diseases is unknown. Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting an estimated 150,000 patients. The disease is caused by missense mutations in Mefv that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that Clostridium difficile infection of FMF knock-in macrophages that express a chimeric FMF-associated MefvV726A Pyrin elicited pyroptosis and gasdermin D (GSDMD)–mediated interleukin (IL)-1β secretion. Importantly, in vivo GSDMD deletion abolished spontaneous autoinflammatory disease. GSDMD-deficient FMF knock-in mice were fully protected from the runted growth, anemia, systemic inflammatory cytokine production, neutrophilia, and tissue damage that characterize this autoinflammatory disease model. Overall, this work identifies pyroptosis as a critical mechanism of IL-1β–dependent autoinflammation in FMF and highlights GSDMD inhibition as a potential antiinflammatory strategy in inflammasome-driven diseases.
DOI: 10.1084/jem.20172060
Institutions: Boston Children's Hospital, Harvard University, Vlaams Instituut voor Biotechnologie, Ghent University, Massachusetts General Hospital, Dana-Farber/Harvard Cancer Center, VIB-UGent Center for Inflammation Research, Center for Computational and Integrative Biology, Massachusetts General Hospital, St. Jude Children's Research Hospital, Broad Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funder: H2020 European Research Council
OpenAlex ID: W2804618431