AMPK integrates metabolite and kinase-based immunometabolic control in macrophages
File(s)
Published version
Author(s)
Type
Journal Article
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.
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.
Date Issued
2023-02-01
Date Acceptance
2022-12-16
Citation
Molecular Metabolism, 2023, 68
ISSN
2212-8778
Publisher
Elsevier BV
Journal / Book Title
Molecular Metabolism
Volume
68
Copyright Statement
© 2022 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/36586434
PII: S2212-8778(22)00230-7
Subjects
A769662
AMPK
Arginine
Cholesterol
Glucose
Immunometabolism
Itaconate
Macrophages
Metformin
Prostaglandins
AMP-Activated Protein Kinases
Macrophages
Succinates
Signal Transduction
Publication Status
Published
Coverage Spatial
Germany
Article Number
101661
Date Publish Online
2022-12-28