Itaconate modulates immune responses via inhibition of peroxiredoxin 5.

The immunoregulatory metabolite itaconate accumulates in innate immune cells upon Toll-like receptor stimulation. In response to macrophage activation by lipopolysaccharide, itaconate inhibits inflammasome activation and boosts type I interferon signalling; however, the molecular mechanism of this immunoregulation remains unclear. Here, we show that the enhancement of type I interferon secretion by itaconate depends on the inhibition of peroxiredoxin 5 and 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 manipulation, we confirm that peroxiredoxin 5 modulates type I interferon secretion in macrophages. The non-electrophilic itaconate mimetic 2-methylsuccinate inhibits peroxiredoxin 5 and phenocopies immunoregulatory action of itaconate on type I interferon and inflammasome activation, providing further support for a non-covalent inhibition of peroxiredoxin 5 by itaconate. Our work provides insight into the molecular mechanism of actions and biological rationale for the predominantly immune specification of itaconate.