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
Affiliations
Alastair J. Hayes
University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Clinical Surgery, University of Edinburgh, Edinburgh, UK
Xiaozhong Zheng
University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
James O’Kelly
University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Clinical Surgery, University of Edinburgh, Edinburgh, UK
Lucile P.A. Neyton
University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; The Roslin Institute, University of Edinburgh, Edinburgh, UK
Natalia A. Bochkina
School of Mathematics and Maxwell Institute, University of Edinburgh, Edinburgh, UK
Iain Uings
GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, UK
John Liddle
GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, UK
J. Kenneth Baillie
The Roslin Institute, University of Edinburgh, Edinburgh, UK
George Just
Mass Spectrometry Core, Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, UK
Margaret Binnie
Mass Spectrometry Core, Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, UK
Natalie Z.M. Homer
Mass Spectrometry Core, Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, UK
Toby B.J. Murray
Clinical Surgery, University of Edinburgh, Edinburgh, UK
James Baily
Charles River Laboratories, East Lothian, UK
Kris McGuire
University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
Christos Skouras
Clinical Surgery, University of Edinburgh, Edinburgh, UK
O. James Garden
Clinical Surgery, University of Edinburgh, Edinburgh, UK
Scott P. Webster
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
John P. Iredale
University of Bristol, Bristol, UK
Sarah E.M. Howie
University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
Damian J. Mole
University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Clinical Surgery, University of Edinburgh, Edinburgh, UK; Corresponding author
Summary: 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.