Vaccines targeting the inflammasome protein ASC reduce inflammation and downstream pathology in multiple disease...

The inflammasome is an innate immune complex responsible for aberrant interleukin-1β (IL-1β) signaling in numerous chronic inflammatory diseases, including gout and Alzheimer's disease. The inflammasome is composed of several proteins, including the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). We developed vaccines targeting various regions of ASC using a Qβ virus-like particle (VLP) platform to assess the efficacy of anti-ASC antibodies for inhibiting inflammasome activity. Using a mouse model of gout, we assessed seven vaccines targeting mouse ASC for their ability to reduce inflammasome activation and neutrophil responses. Three vaccines targeting different regions of the ASC protein (pyrin domain, linker region, and the caspase activation and recruitment domain) successfully targeted ASC, reduced IL-1β, and reduced neutrophil activation. Combining these three vaccines into one cocktail vaccine yielded similar efficacy in the gout model with a favorable safety profile. The combined ASC vaccine also reduced inflammasome levels and pathologically phosphorylated tau in a transgenic mouse model of tauopathy and did not significantly impair host immune responses to bacterial or viral infections. Thus, Qβ-VLP vaccines against ASC can neutralize pathological inflammasome activity across multiple inflammatory disease models.