Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis

Alastair J Hayes, Xiaozhong Zheng, James O'Kelly, Lucile P A Neyton, Natalia A Bochkina, Iain Uings, John Liddle, J Kenneth Baillie, George Just, Margaret Binnie, Natalie Z M Homer, Toby B J Murray, James Baily, Kris McGuire, Christos Skouras, O James Garden, Scott P Webster, John P Iredale, Sarah E M Howie, Damian J Mole

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1β to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.

Original languageEnglish
Article number112763
Pages (from-to)1-23
Number of pages23
JournalCell Reports
Issue number8
Early online date19 Jul 2023
Publication statusPublished - 29 Aug 2023

Keywords / Materials (for Non-textual outputs)

  • 3-hydroxykynurenine
  • CP: Metabolism
  • acute pancreatitis
  • critical illness
  • kynurenine 3-monooxygenase
  • metabolomics
  • multiple organ failure
  • transcriptome


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