IFN-α and IFN-β inhibit NLRP1-driven PANoptosis.

Abstract

Pathogens, tissue damage, and cellular stress are detected by innate immune sensor molecules to drive inflammatory signaling and cell death. Mutations in the sensor NLRP1 are associated with inflammatory disease, but the regulation of this sensor is not well understood. Here, we find that LPS, a TLR4 ligand and canonical activator of innate immunity, inhibits NLRP1-mediated caspase activation, IL-18 release, and inflammatory cell death, PANoptosis. This inhibition requires TRIF but not MyD88, implicating TRIF-dependent TLR signaling. IRF3 is also required, suggesting an essential role for type I IFN signaling. Indeed, IFN-β production or treatment with exogenous IFN-α or IFN-β inhibits NLRP1-dependent PANoptosis in mouse bone marrow-derived macrophages and human macrophages and monocytes. Mechanistically, Nlrp1b/NLRP1 expression is significantly reduced in LPS- or type I IFN-treated cells. Overall, our study identifies a TLR4-TRIF-IRF3 signaling axis that induces type I IFNs to negatively regulate NLRP1 transcription, thereby blocking NLRP1-driven, caspase-1/caspase-8/RIPK3-dependent PANoptosis. These findings suggest type I IFNs as a potential therapeutic strategy for NLRP1-driven inflammatory diseases.