Inflammasome genetics affect several multifactorial diseases' development and severity, but the exact mechanism and cell types involved are mainly unknown. Recent findings have demonstrated the activation of caspase-1 and the release of IL-1β in B lymphocytes, leading us to hypothesize that genetic variants within the inflammasome may influence B cell functions and contribute to pathological immune responses. We previously reported the significance of NLRP3 and its variants in the dysregulation of B cells during chronic HIV infection. Here, we demonstrate that the inflammasome activation in human CD19+ cells is influenced by NLRP1 genetic variants yet associated with B cell-mediated diseases. The DPP-9 inhibitor ValBoro-Pro (VbP; Talabostat) was used to stimulate the two inflammasome sensors, NLRP1 and CARD8. First, we demonstrated that VbP induces caspase-1-dependent pyroptosis, but not IL-1β release, in CD19+ cells. Then, we evaluated the impact of common functional variants in NLRP1 and CARD8 genes on inflammasome activation in those cells. Therefore, our study identifies NLRP1 missense variants that impact B lymphocyte response to DPP9 inhibition. This implies a potential direct association between NLRP1 variants, B cell-mediated diseases, such as autoimmune and allergic conditions, and cancer.
