Lipids in inflammasome activation and autoinflammatory disorders

Autoinflammatory diseases (AIDs) are a group of rare monogenetic disorders characterized by recurrent episodes of fever and systemic inflammation. A major pathologic hallmark of AIDs is excessive inflammasome assembly and activation, often the result of gain-of-function mutations in genes encoding core inflammasome components, including pyrin and cryopyrin. Recent advances in lipidomics have revealed that dysregulated metabolism of lipids such as cholesterol and fatty acids, especially in innate immune cells, exerts complex effects on inflammasome activation and the pathogenesis of AIDs. In this review, we summarize and discuss the impact of lipids and their metabolism on inflammasome activation and the disease pathogenesis of the most common AIDs, including familial Mediterranean fever, cryopyrin-associated periodic syndromes, and mevalonate kinase deficiency. We postulate that lipids hold diagnostic value in AIDs and that dietary and pharmacologic intervention studies could represent a promising approach to attenuate inflammasome activation and AID progression.