GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• Familial Mediterranean Fever (FMF) is a common monogenic autoinflammatory disease caused by MEFV mutations activating the Pyrin inflammasome.
• The precise mechanisms driving FMF pathogenesis remain incompletely understood.
• Pyroptosis, an inflammasome-regulated cell death, is implicated in inflammatory diseases.

Purpose of the Study:

• To investigate the role of pyroptosis and gasdermin D (GSDMD) in FMF pathogenesis.
• To determine if GSDMD inhibition can ameliorate FMF-associated autoinflammatory disease.

Main Methods:

• Utilized FMF knock-in mouse models expressing a chimeric MEFV V726A Pyrin.
• Infected macrophages with Clostridium difficile to induce pyroptosis and IL-1β secretion.
• Generated GSDMD-deficient FMF knock-in mice to assess disease protection.

Main Results:

• FMF macrophages exhibited pyroptosis and GSDMD-mediated IL-1β secretion upon C. difficile infection.
• In vivo GSDMD deletion completely abolished spontaneous autoinflammatory disease in FMF mice.
• GSDMD-deficient FMF mice were protected from growth retardation, anemia, inflammation, neutrophilia, and tissue damage.

Conclusions:

• Pyroptosis is a key mechanism driving IL-1β-dependent autoinflammation in FMF.
• GSDMD is essential for FMF pathogenesis.
• GSDMD inhibition represents a promising anti-inflammatory strategy for FMF and other inflammasome-driven autoinflammatory diseases.