PAD4-generated citrullinated histones are triggers for autoinflammation in cryopyrin-associated periodic syndrome

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory diseases linked to NLRP3 gene variants.
• NLRP3 inflammasomes typically mediate IL-1β secretion via Gasdermin D (GSDMD).

Purpose of the Study:

• To investigate the mechanisms of autoinflammation in CAPS, particularly the role of GSDMD-independent pathways.
• To identify novel triggers and mediators of IL-1β secretion in CAPS.

Main Methods:

• Utilized mice models with ubiquitous and neutrophil-specific Nlrp3^A350V expression, including GSDMD-deficient and GSDME-deficient variants.
• Analyzed neutrophil extracellular traps (NETs), citrullinated histone 3 (CitH3), and IL-1β secretion in macrophages and monocytes from mice and CAPS patients.
• Investigated the role of protein arginine deiminase-4 (PAD4) in CitH3 release and its impact on autoinflammation.

Main Results:

• GSDMD deletion did not prevent autoinflammation in Nlrp3^A350V mice, indicating GSDMD-independent pathways.
• CitH3-NETs were identified in inflamed skin and induced IL-1β secretion in a GSDMD-deficient context.
• Blocking PAD4 inhibited CitH3 release and IL-1β secretion, while GSDME activation was crucial for pathology in GSDMD-deficient models.
• PAD4 inhibition also ameliorated CAPS in GSDMD-dependent models.

Conclusions:

• PAD4-mediated CitH3-NET release is a key driver of autoinflammation in CAPS.
• Both GSDMD-dependent and GSDME-dependent pathways, triggered by CitH3-NETs, contribute to CAPS pathogenesis.
• Targeting PAD4 and CitH3-NETs presents a potential therapeutic strategy for CAPS.