Adenosine and Purinergic Signaling
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It is reported that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.
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Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.
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@article{TollerKawahisa2025Metabolic,
title = {Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine},
author = {Juliana E. Toller-Kawahisa and Paula Ramos Viacava and Eva M. Pålsson‐McDermott and Daniele C. Nascimento and Mariana P. Cervantes‐Silva and Shane M. O’Carroll and Alessia Zotta and Luis Eduardo Alves Damasceno and Gabriel Azevedo Públio and Pedro K K Forti and João Paulo Mesquita Luiz and Bruno Marcel Silva de Melo and Timna Varela Martins and Vítor M. Faça and Annie M. Curtis and Thiago M. Cunha and Fernando Q. Cunha and Luke O'neill and José C. Alves‐Filho},
journal = {Cell Reports},
year = {2025},
doi = {10.1016/j.celrep.2024.115172},
url = {https://doi.org/10.1016/j.celrep.2024.115172}
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