GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever.
Apurva KannegantiR K Subbarao MalireddiPedro H V SaavedraLieselotte Vande WalleHanne Van GorpHiroto KambaraHeather TillmanPeter VogelHongbo R LuoRamnik J XavierHongbo ChiMohamed LamkanfiPublished in: The Journal of experimental medicine (2018)
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.
Keyphrases
- cell death
- mouse model
- oxidative stress
- end stage renal disease
- chronic kidney disease
- nlrp inflammasome
- gene expression
- early onset
- ejection fraction
- dna methylation
- stem cells
- genome wide
- type diabetes
- peritoneal dialysis
- adipose tissue
- mesenchymal stem cells
- skeletal muscle
- endothelial cells
- patient reported
- autism spectrum disorder
- stress induced
- diabetic rats