AMPK integrates metabolite and kinase-based immunometabolic control in macrophages

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 AMPKa1.Results: Comparing macrophages with AMPKa1 catalytic subunit deletion with wild-type, inflammatory markers are largely unchanged in unstimulated cells, but with an LPS stimulus, AMPKa1 knockout leads to a striking M1 hyperpolarisation. Deletion of AMPKa1 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 AMPKa1 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.(c) 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/).

Automated summary

This study demonstrates the integration of metabolite and kinase-based immunometabolic control in macrophages through the activation of AMP kinase. The deletion of AMPKa1 leads to a striking polarization of M1 macrophages upon LPS stimulation, along with increased expression of rate-limiting enzymes involved in various metabolic pathways.