@article{ec80755cbc2d4037a5dbdcf484e0aa90,
title = "Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis",
abstract = "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.",
keywords = "3-hydroxykynurenine, CP: Metabolism, acute pancreatitis, critical illness, kynurenine 3-monooxygenase, metabolomics, multiple organ failure, transcriptome",
author = "Hayes, {Alastair J} and Xiaozhong Zheng and James O'Kelly and Neyton, {Lucile P A} and Bochkina, {Natalia A} and Iain Uings and John Liddle and Baillie, {J Kenneth} and George Just and Margaret Binnie and Homer, {Natalie Z M} and Murray, {Toby B J} and James Baily and Kris McGuire and Christos Skouras and Garden, {O James} and Webster, {Scott P} and Iredale, {John P} and Howie, {Sarah E M} and Mole, {Damian J}",
note = "Funding Information: We wish to thank Dr. Forbes Howie, Shonna Johnson, Dr. William Ramage, and Will Mongall from the University of Edinburgh for their technical assistance. We thank the Named Veterinary Surgeons of the University of Edinburgh for their guidance. We thank Dr. Stuart Hayes of the Anatomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Germany, for training A.J.H. in scientific Python programming for data visualization. A.J.H. and J.O. were funded by the Amelie Waring Fellowship from Guts UK Charity (formerly Core). The University of Edinburgh/GSK have a Discovery Partnership with Academia collaboration. L.P.A.N. holds a Doctoral Training Program PhD studentship from the Medical Research Council. T.B.J.M. was funded by a research bursary from the Royal College of Surgeons of England. J.K.B. is funded by a Wellcome Trust Intermediate Clinical Fellowship (103258/Z/13/Z), a Wellcome-Beit Prize (103258/Z/13/A), a BBSRC Institute Strategic Program Grant to the Roslin Institute, and the UK Intensive Care Society. D.J.M. holds a Senior Clinical Fellowship from the UK Medical Research Council (MR/P008887/1). Conceptualization, A.J.H. and D.J.M.; methodology, A.J.H. X.Z. T.B.J.M. G.J. N.A.B. and D.J.M.; software, A.J.H. and L.P.A.N.; formal analysis, A.J.H. N.A.B. and D.J.M.; investigation, A.J.H. X.Z. J.O. J.K.B. T.B.J.M. M.B. and G.J.; writing – original draft, A.J.H. I.U. and D.J.M.; writing – review & editing, A.J.H. I.U. K.M. N.A.B. J.K.B. C.S. N.Z.M.H. O.J.G. J.P.I. and D.J.M.; visualization, A.J.H. and L.P.A.N.; project administration, A.J.H. and D.J.M.; resources, A.J.H. X.Z. I.U. J.L. and D.J.M.; supervision, S.E.M.H. J.P.I. and D.J.M.; funding acquisition, A.J.H. O.J.G. J.P.I. and D.J.M. S.P.W. and D.J.M. are co-founders of Kynos Therapeutics, Ltd. D.J.M. is a board member of Kynos. The University of Edinburgh controls patents WO2015/091647, WO2016/097144, and WO2016/188827, which relate to inhibitors of KMO and include the compound used in this paper. We support inclusive, diverse, and equitable conduct of research. Funding Information: We wish to thank Dr. Forbes Howie, Shonna Johnson, Dr. William Ramage, and Will Mongall from the University of Edinburgh for their technical assistance. We thank the Named Veterinary Surgeons of the University of Edinburgh for their guidance. We thank Dr. Stuart Hayes of the Anatomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Germany, for training A.J.H. in scientific Python programming for data visualization. A.J.H. and J.O. were funded by the Amelie Waring Fellowship from Guts UK Charity (formerly Core). The University of Edinburgh/GSK have a Discovery Partnership with Academia collaboration. L.P.A.N. holds a Doctoral Training Program PhD studentship from the Medical Research Council. T.B.J.M. was funded by a research bursary from the Royal College of Surgeons of England . J.K.B. is funded by a Wellcome Trust Intermediate Clinical Fellowship ( 103258/Z/13/Z ), a Wellcome-Beit Prize ( 103258/Z/13/A ), a BBSRC Institute Strategic Program Grant to the Roslin Institute , and the UK Intensive Care Society . D.J.M. holds a Senior Clinical Fellowship from the UK Medical Research Council ( MR/P008887/1 ). Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = aug,
day = "29",
doi = "10.1016/j.celrep.2023.112763",
language = "English",
volume = "42",
pages = "1--23",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}