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SHR Neuro Cancer Cardio Lipid Metab Microb

Papadopoulou, G; Valakos, D; Polydouri, I; Moulara, A; Vatsellas, G; Angiari, S; Runtsch, MC; Foretz, M; Viollet, B; Cassotta, A; O'Neill, LAJ; Xanthou, G.
Adenosine 2A receptor-dependent activation of AMPK represses T_H17 cell pathogenicity through epigenetic and metabolic reprogramming.
Sci Signal. 2025; 18(905):eadr3177 Doi: 10.1126/scisignal.adr3177
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Co-authors Med Uni Graz: Angiari Stefano; Runtsch Marah
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Abstract:: Metabolic reprogramming controls protective and pathogenic T helper 17 (T_H17) cell responses. When naïve T cells are differentiated into T_H17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic T_H17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A_2A receptor (A_2AR) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic T_H17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic T_H17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys⁹ (H3K9ac) of genes involved in aerobic glycolysis and T_H17 pathogenic programs. In contrast, in nonpathogenic activin A-treated T_H17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic T_H17 programs. Together, our findings uncover A_2AR-AMPK signaling as a central metabolic checkpoint that suppresses T_H17 cell pathogenicity.
Find related publications in this database (using NLM MeSH Indexing): Animals - administration & dosage; Receptor, Adenosine A2A - metabolism, immunology, genetics; Th17 Cells - immunology, metabolism, pathology; AMP-Activated Protein Kinases - metabolism, genetics, immunology; Mice - administration & dosage; Epigenesis, Genetic - immunology; Signal Transduction - immunology; Histones - metabolism; Oxidative Phosphorylation - administration & dosage; Glycolysis - administration & dosage; Mice, Inbred C57BL - administration & dosage; p300-CBP Transcription Factors - metabolism, genetics, immunology; Multiple Sclerosis - immunology, metabolism, pathology, genetics; Encephalomyelitis, Autoimmune, Experimental - immunology, pathology, metabolism; Cell Differentiation - administration & dosage; Acetylation - administration & dosage; Metabolic Reprogramming - administration & dosage

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