NLRC4 inhibits NLRP3 inflammasome and abrogates effective antifungal CD8+ T cell responses

The recognition of fungi by intracellular NOD-like receptors (NLRs) induces in-flammasome assembly and activation. Although the NLRC4 inflammasome has been extensively studied in bacterial infections, its role during fungal infections is unclear. Paracoccidioidomycosis (PCM) is a pathogenic fungal disease caused by Paracoccidioides brasiliensis. Here, we showthatNLRC4 confers susceptibility to experimental PCM by regulating NLRP3-dependent cytokine production and thus protective effector mechanisms. Early after infection, NLRC4 suppresses prostaglandin E-2 production, and consequently reduces interleukin (IL)-1 beta release by macrophages and dendritic cells in the lungs. IL-1 beta is required to control fungal replication via induction of the nitric oxide synthase 2 (NOS2) pathway. At a later stage of the disease, NLRC4 impacts IL-18 release, dampening robust CD8(+)IFN-gamma(+) T cell responses and enhancing mortality of mice. These findings demonstrate that NLRC4 promotes disease by regulating the production of inflammatory cytokines and cellular responses that depend on the NLRP3 inflammasome activity.

Automated summary

The NLR molecule NLRC4 has been found to promote susceptibility to experimental PCM by regulating cytokine production and protective effector mechanisms. It suppresses prostaglandin E-2 production early in infection, reducing IL-1 beta release and impacting IL-18 release later in the disease, ultimately affecting immune responses and mortality.