AMPK integrates metabolite and kinase-based immunometabolic control in macrophages

Iain R. Phair; Raid B. Nisr; Andrew J. M. Howden; Magdalena Sovakova; Noor Alqurashi; Marc Foretz; Douglas Lamont; Benoit Viollet; Graham Rena

doi:10.1016/j.molmet.2022.101661

AMPK integrates metabolite and kinase-based immunometabolic control in macrophages

Iain R. Phair (Lead / Corresponding author), Raid B. Nisr, Andrew J. M. Howden, Magdalena Sovakova, Noor Alqurashi, Marc Foretz, Douglas Lamont, Benoit Viollet, Graham Rena (Lead / Corresponding author)

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Abstract

Objective: Previous mechanistic studies on immunometabolism have focused on metabolite-based paradigms of regulation, such as itaconate. Here, we, demonstrate integration of metabolite and kinase-based immunometabolic control by AMP kinase.

Methods: We combined whole cell quantitative proteomics with gene knockout of AMPKα1.

Results: Comparing macrophages with AMPKα1 catalytic subunit deletion with wild-type, inflammatory markers are largely unchanged in unstimulated cells, but with an LPS stimulus, AMPKα1 knockout leads to a striking M1 hyperpolarisation. Deletion of AMPKα1 also resulted in increased expression of rate-limiting enzymes involved in itaconate synthesis, metabolism of glucose, arginine, prostaglandins and cholesterol. Consistent with this, we observed functional changes in prostaglandin synthesis and arginine metabolism. Selective AMPKα1 activation also unlocks additional regulation of IL-6 and IL-12 in M1 macrophages.

Conclusions: Together, our results validate AMPK as a pivotal immunometabolic regulator in macrophages.

Original language	English
Article number	101661
Number of pages	15
Journal	Molecular Metabolism
Volume	68
Early online date	28 Dec 2022
DOIs	https://doi.org/10.1016/j.molmet.2022.101661
Publication status	Published - Feb 2023

Keywords

AMPK
Metformin
A769662
Macrophages
Immunometabolism
Itaconate
Prostaglandins
Glucose
Cholesterol
Arginine

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10.1016/j.molmet.2022.101661Licence: CC BY

Final Published VersionFinal published version, 3.19 MBLicence: CC BY

Cite this

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title = "AMPK integrates metabolite and kinase-based immunometabolic control in macrophages",

abstract = "Objective: Previous mechanistic studies on immunometabolism have focused on metabolite-based paradigms of regulation, such as itaconate. Here, we, demonstrate integration of metabolite and kinase-based immunometabolic control by AMP kinase.Methods: We combined whole cell quantitative proteomics with gene knockout of AMPKα1.Results: Comparing macrophages with AMPKα1 catalytic subunit deletion with wild-type, inflammatory markers are largely unchanged in unstimulated cells, but with an LPS stimulus, AMPKα1 knockout leads to a striking M1 hyperpolarisation. Deletion of AMPKα1 also resulted in increased expression of rate-limiting enzymes involved in itaconate synthesis, metabolism of glucose, arginine, prostaglandins and cholesterol. Consistent with this, we observed functional changes in prostaglandin synthesis and arginine metabolism. Selective AMPKα1 activation also unlocks additional regulation of IL-6 and IL-12 in M1 macrophages.Conclusions: Together, our results validate AMPK as a pivotal immunometabolic regulator in macrophages.",

keywords = "AMPK, Metformin, A769662, Macrophages, Immunometabolism, Itaconate, Prostaglandins, Glucose, Cholesterol, Arginine",

author = "Phair, {Iain R.} and Nisr, {Raid B.} and Howden, {Andrew J. M.} and Magdalena Sovakova and Noor Alqurashi and Marc Foretz and Douglas Lamont and Benoit Viollet and Graham Rena",

note = "Funding Information: GR acknowledges research grants from Academy of Medical Sciences NIF∖R5A∖0017, British Heart Foundation PG/18/79/34106 and Diabetes UK 19/0006045. Copyright: {\textcopyright} 2022 The Authors. Published by Elsevier GmbH..",

year = "2023",

month = feb,

doi = "10.1016/j.molmet.2022.101661",

language = "English",

volume = "68",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

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TY - JOUR

T1 - AMPK integrates metabolite and kinase-based immunometabolic control in macrophages

AU - Phair, Iain R.

AU - Nisr, Raid B.

AU - Howden, Andrew J. M.

AU - Sovakova, Magdalena

AU - Alqurashi, Noor

AU - Foretz, Marc

AU - Lamont, Douglas

AU - Viollet, Benoit

AU - Rena, Graham

N1 - Funding Information: GR acknowledges research grants from Academy of Medical Sciences NIF∖R5A∖0017, British Heart Foundation PG/18/79/34106 and Diabetes UK 19/0006045. Copyright: © 2022 The Authors. Published by Elsevier GmbH..

PY - 2023/2

Y1 - 2023/2

N2 - Objective: Previous mechanistic studies on immunometabolism have focused on metabolite-based paradigms of regulation, such as itaconate. Here, we, demonstrate integration of metabolite and kinase-based immunometabolic control by AMP kinase.Methods: We combined whole cell quantitative proteomics with gene knockout of AMPKα1.Results: Comparing macrophages with AMPKα1 catalytic subunit deletion with wild-type, inflammatory markers are largely unchanged in unstimulated cells, but with an LPS stimulus, AMPKα1 knockout leads to a striking M1 hyperpolarisation. Deletion of AMPKα1 also resulted in increased expression of rate-limiting enzymes involved in itaconate synthesis, metabolism of glucose, arginine, prostaglandins and cholesterol. Consistent with this, we observed functional changes in prostaglandin synthesis and arginine metabolism. Selective AMPKα1 activation also unlocks additional regulation of IL-6 and IL-12 in M1 macrophages.Conclusions: Together, our results validate AMPK as a pivotal immunometabolic regulator in macrophages.

AB - Objective: Previous mechanistic studies on immunometabolism have focused on metabolite-based paradigms of regulation, such as itaconate. Here, we, demonstrate integration of metabolite and kinase-based immunometabolic control by AMP kinase.Methods: We combined whole cell quantitative proteomics with gene knockout of AMPKα1.Results: Comparing macrophages with AMPKα1 catalytic subunit deletion with wild-type, inflammatory markers are largely unchanged in unstimulated cells, but with an LPS stimulus, AMPKα1 knockout leads to a striking M1 hyperpolarisation. Deletion of AMPKα1 also resulted in increased expression of rate-limiting enzymes involved in itaconate synthesis, metabolism of glucose, arginine, prostaglandins and cholesterol. Consistent with this, we observed functional changes in prostaglandin synthesis and arginine metabolism. Selective AMPKα1 activation also unlocks additional regulation of IL-6 and IL-12 in M1 macrophages.Conclusions: Together, our results validate AMPK as a pivotal immunometabolic regulator in macrophages.

KW - AMPK

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KW - A769662

KW - Macrophages

KW - Immunometabolism

KW - Itaconate

KW - Prostaglandins

KW - Glucose

KW - Cholesterol

KW - Arginine

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SN - 2212-8778

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AMPK integrates metabolite and kinase-based immunometabolic control in macrophages

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Relative Contributions of Fructose Bisphosphatase-1 (FBP1) and Other Possible Mediators to the Antihyperglycaemic Action of Salicylate

Immunometabolic Remodelling of Monocyte and Macrophage Responses by Metformin in Non-diabetic CVD

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AMPK integrates metabolite and kinase-based immunometabolic control in macrophages

Abstract

Keywords

Access to Document

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Relative Contributions of Fructose Bisphosphatase-1 (FBP1) and Other Possible Mediators to the Antihyperglycaemic Action of Salicylate

Immunometabolic Remodelling of Monocyte and Macrophage Responses by Metformin in Non-diabetic CVD

Cite this