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<p>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.</p>

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Itaconate modulates immune responses via inhibition of peroxiredoxin 5

  • 期刊论文

  • 发表日期：

    2025年4月18日

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  • Tomas Paulenda,
  • Barbora Echalar,
  • Lucie Potuckova,
  • Veronika Vachova,
  • Denis A. Kleverov,
  • Johannes Mehringer,
  • Ekaterina Potekhina,
  • Alex Jacoby,
  • Devashish Sen,
  • Chris Nelson,
  • Rick Stegeman,
  • Vladimir Sukhov,
  • Danielle Kemper,
  • Cheryl F. Lichti,
  • Nicholas J. Day,
  • Tong Zhang,
  • Kamila Husarcikova,
  • Monika Bambouskova,
  • Daved H. Fremont,
  • Wei-jun Qian,
  • Sergej Djuranovic,
  • Slavica Pavlovic-Djuranovic,
  • Vsevolod V. Belousov,
  • Andrzej M. Krezel,
  • Maxim N. Artyomov

摘要

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.