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

• DOI: 10.1016/j.celrep.2023.112763
• Publication Date: 2023-07-19T22:17:54Z
• Authors: 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
• Keywords: Mice, Knockout; Inflammation; acute pancreatitis; multiple organ failure; QH301-705.5; Critical Illness; Multiple Organ Failure; 3-hydroxykynurenine; metabolomics; CP: Metabolism; 3. Good health; kynurenine 3-monooxygenase; Mice; Kynurenine 3-Monooxygenase; Pancreatitis; Metabolism [CP]; Acute Disease; critical illness; Animals; Biology (General); transcriptome; Kynurenine

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.