Projects per year
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.
Original language | English |
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Article number | 112763 |
Pages (from-to) | 1-23 |
Number of pages | 23 |
Journal | Cell Reports |
Volume | 42 |
Issue number | 8 |
Early online date | 19 Jul 2023 |
DOIs | |
Publication status | Published - 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
Fingerprint
Dive into the research topics of 'Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis'. Together they form a unique fingerprint.Projects
- 2 Finished
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Premature death and organ hypofunction after severe acute pancreatitis results from cellular senescence - mechanisms and new opportunities for therapy
Mole, D. (Principal Investigator)
1/02/17 → 31/01/23
Project: Research
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Identification and characterisation of host factors underlying susceptibility to influenza
Baillie, K. (Principal Investigator)
1/08/14 → 1/02/20
Project: Research
Equipment
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Edinburgh Clinical Research Facility Mass Spectrometry Core in the QMRI
Homer, N. (Manager), Denham, S. (Other) & Simpson, J. (Other)
Centre for Cardiovascular ScienceFacility/equipment: Facility
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Edinburgh Drug Discovery
Unciti-Broceta, A. (Manager), Webster, S. (Manager) & Carragher, N. (Manager)
Deanery of Molecular, Genetic and Population Health SciencesFacility/equipment: Facility