-Itaconate confers tolerance to late NLRP3 inflammasome activation

Abstract Itaconate is a unique regulatory metabolite that induced upon toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production activated macrophages. We show endogenous key regulator of the signal 2 NLRP3 inflammasome activation after long LPS priming which establishes to late activation. acts synergistically iNOS ability various TLR ligands establish depends on pattern co-expression IRG1 iNOS. Mechanistically, accumulation prolonged prevents full caspase-1 processing gasdermin D, be post-translationally modified by itaconate. Altogether, our data metabolic rewiring macrophages which, if uncontrolled, can result pyroptotic tissue damage.