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

doi:10.1016/j.celrep.2023.112763

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 journal › Article › peer-review

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
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	https://doi.org/10.1016/j.celrep.2023.112763
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

Access to Document

10.1016/j.celrep.2023.112763

1-s2.0-S221112472300774X-mainFinal published version, 8.72 MBLicence: CC BY-NC-ND

Premature death and organ hypofunction after severe acute pancreatitis results from cellular senescence - mechanisms and new opportunities for therapy
Mole, D. (Principal Investigator)
MRC
1/02/17 → 31/01/23
Project: Research
Identification and characterisation of host factors underlying susceptibility to influenza
Baillie, K. (Principal Investigator)
UK-based charities
1/08/14 → 1/02/20
Project: Research

Edinburgh Clinical Research Facility Mass Spectrometry Core in the QMRI
Homer, N. (Manager), Denham, S. (Other) & Simpson, J. (Other)
Centre for Cardiovascular Science
Facility/equipment: Facility
Edinburgh Drug Discovery
Unciti-Broceta, A. (Manager), Webster, S. (Manager) & Carragher, N. (Manager)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

Hayes, A. J., Zheng, X., O'Kelly, J., Neyton, L. P. A., Bochkina, N. A., Uings, I., Liddle, J., Baillie, J. K., Just, G., Binnie, M., Homer, N. Z. M., Murray, T. B. J., Baily, J., McGuire, K., Skouras, C., Garden, O. J., Webster, S. P., Iredale, J. P., Howie, S. E. M., & Mole, D. J. (2023). Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis. Cell Reports, 42(8), 1-23. Article 112763. https://doi.org/10.1016/j.celrep.2023.112763

@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",

}

Hayes, AJ, Zheng, X, O'Kelly, J, Neyton, LPA, Bochkina, NA, Uings, I, Liddle, J, Baillie, JK, Just, G, Binnie, M, Homer, NZM, Murray, TBJ, Baily, J, McGuire, K, Skouras, C, Garden, OJ , Webster, SP, Iredale, JP, Howie, SEM & Mole, DJ 2023, 'Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis', Cell Reports, vol. 42, no. 8, 112763, pp. 1-23. https://doi.org/10.1016/j.celrep.2023.112763

TY - JOUR

T1 - Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis

AU - Hayes, Alastair J

AU - Zheng, Xiaozhong

AU - O'Kelly, James

AU - Neyton, Lucile P A

AU - Bochkina, Natalia A

AU - Uings, Iain

AU - Liddle, John

AU - Baillie, J Kenneth

AU - Just, George

AU - Binnie, Margaret

AU - Homer, Natalie Z M

AU - Murray, Toby B J

AU - Baily, James

AU - McGuire, Kris

AU - Skouras, Christos

AU - Garden, O James

AU - Webster, Scott P

AU - Iredale, John P

AU - Howie, Sarah E M

AU - Mole, Damian J

N1 - 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: © 2023 The Author(s)

PY - 2023/8/29

Y1 - 2023/8/29

N2 - 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.

AB - 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.

KW - 3-hydroxykynurenine

KW - CP: Metabolism

KW - acute pancreatitis

KW - critical illness

KW - kynurenine 3-monooxygenase

KW - metabolomics

KW - multiple organ failure

KW - transcriptome

U2 - 10.1016/j.celrep.2023.112763

DO - 10.1016/j.celrep.2023.112763

M3 - Article

C2 - 37478012

SN - 2211-1247

VL - 42

SP - 1

EP - 23

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 112763

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

Premature death and organ hypofunction after severe acute pancreatitis results from cellular senescence - mechanisms and new opportunities for therapy

Identification and characterisation of host factors underlying susceptibility to influenza

Equipment

Edinburgh Clinical Research Facility Mass Spectrometry Core in the QMRI

Edinburgh Drug Discovery

Cite this