NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminth Schistosoma mansoni.

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 severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types of caspases and inflammasomes involved, nor their impact on the Th17 response are known. Here we show that enhanced egg-induced IL-1ß secretion and pyroptotic cell death required both caspase-1 and caspase-8 as well as NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, potassium efflux and cathepsin B, were the major activators of NLRP3. NLRP3 and AIM2 deficiency led to a significant reduction in pathogenic Th17 responses, suggesting their crucial and non-redundant role in promoting inflammation. Additionally, we show that NLRP3- and AIM2-induced IL-1ß suppressed IL-4 and protective Type I IFN (IFN-I) production, which further enhanced inflammation. IFN-I signaling also curbed inflammasome- mediated IL-1ß production suggesting that these two antagonistic pathways shape the severity of disease. Lastly, Gasdermin D (Gsdmd) deficiency resulted in a marked decrease in egg-induced granulomatous inflammation. Our findings establish NLRP3/AIM2-Gsdmd axis as a central inducer of pathogenic Th17 responses which is counteracted by IFN-I pathway in schistosomiasis.

The balance between gasdermin D and STING signaling shapes the severity of schistosome immunopathology.

There is significant disease heterogeneity among mouse strains infected with the helminth Schistosoma mansoni. Here, we uncover a unique balance in two critical innate pathways governing the severity of disease. In the low-pathology setting, parasite egg-stimulated dendritic cells (DCs) induce robust interferon (IFN)ß production, which is dependent on the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway and results in a Th2 response with suppression of proinflammatory cytokine production and Th17 cell activation. IFNß induces signal transducer and activator of transcription (STAT)1, which suppresses CD209a, a C-type lectin receptor associated with severe disease. In contrast, in the high-pathology setting, enhanced DC expression of the pore-forming protein gasdermin D (Gsdmd) results in reduced expression of cGAS/STING, impaired IFNß, and enhanced pyroptosis. Our findings demonstrate that cGAS/STING signaling represents a unique mechanism inducing protective type I IFN, which is counteracted by Gsdmd.