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Updated: Jun 3, 2025
Reprograming Model of Human Monocyte-derived Macrophages for In-vitro Assays
Published on: April 18, 2025
Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine
Juliana Escher Toller-Kawahisa1, Paula Ramos Viacava2, Eva Margareta Palsson-McDermott3
1Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; Center for Research in Inflammatory Diseases, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin, Ireland.
Abstract:
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.
