GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever.
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 that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that infection of FMF knock-in macrophages that express a chimeric FMF-associated 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.
|Year of Publication||
J Exp Med
2018 06 04
|PubMed Central ID||
683144 / ERC_ / European Research Council / International
P01 HL095489 / HL / NHLBI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States