NLRP3 and AIM2 inflammasome-triggered Th17 cell response promotes severe immunopathology in schistosomiasis

Abstract

Abstract Infection with the helminth Schistosoma mansoni can cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of increased granulomatous hepatic immunopathology. A role of inflammasomes in intensifying disease has been reported, however, neither the types of inflammasomes involved, nor their impact on the Th17 response are known. Here we show that the observed enhanced egg-induced IL-1β secretion and pyroptotic cell death required both NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, as well as potassium efflux, were the major activators of NLRP3. In addition, dual activation of caspase-1 and caspase-8 was required for egg-induced IL17 production. NLRP3 and AIM2 deficiency led to a significant reduction in Th17 responses, suggesting that both play a crucial role in triggering inflammation. We also determined that inflammasome-induced IL-1β promotes the anti-inflammatory Th2 cytokine IL-4. Our findings establish NLRP3 and AIM2 inflammasomes as central inducers of pathogenic Th17 responses in schistosomiasis.