Itaconate modulates immune responses via inhibition of peroxiredoxin 5 2077

Description Itaconate, an immunoregulatory metabolite, is heavily accumulated in innate immune cells during activation by multiple TLR stimuli. In the context of macrophage activation by LPS it was shown to inhibit inflammasome activation and boost type I interferon signaling; however, the molecular mechanism of immunoregulation remains unclear. To address this question, we focused on type I interferon phenotype, characterized it in depth in the context of both exogenous and endogenous itaconate, and found that enhancement of type I interferon secretion by itaconate relies on mitochondrial reactive oxygen species. We find that itaconate non-covalently inhibits Peroxiredoxin 5, leading to the modulation of mitochondrial peroxide in activating macrophages. Through genetic ablation or overexpression, we confirmed that Peroxiredoxin 5 is a novel regulator of type I interferon secretion in macrophages. The non-covalent nature of the inhibition is further supported by the fact that non-electrophilic itaconate mimetic 2-methylsuccinate inhibits Peroxiredoxin 5 and phenocopies immunoregulatory action of itaconate on type I interferon and inflammasome activation. Our work provides insight into the molecular mechanism of action and biological rationale for predominantly immune specification of itaconate.