Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou
{"title":"腺苷2A受体依赖性激活AMPK通过表观遗传和代谢重编程抑制TH17细胞致病性","authors":"Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou","doi":"10.1126/scisignal.adr3177","DOIUrl":null,"url":null,"abstract":"<div >Metabolic reprogramming controls protective and pathogenic T helper 17 (T<sub>H</sub>17) cell responses. When naïve T cells are differentiated into T<sub>H</sub>17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic T<sub>H</sub>17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic T<sub>H</sub>17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic T<sub>H</sub>17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys<sup>9</sup> (H3K9ac) of genes involved in aerobic glycolysis and T<sub>H</sub>17 pathogenic programs. In contrast, in nonpathogenic activin A–treated T<sub>H</sub>17 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<sub>H</sub>17 programs. Together, our findings uncover A<sub>2A</sub>R-AMPK signaling as a central metabolic checkpoint that suppresses T<sub>H</sub>17 cell pathogenicity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Adenosine 2A receptor–dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming\",\"authors\":\"Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou\",\"doi\":\"10.1126/scisignal.adr3177\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Metabolic reprogramming controls protective and pathogenic T helper 17 (T<sub>H</sub>17) cell responses. When naïve T cells are differentiated into T<sub>H</sub>17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic T<sub>H</sub>17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic T<sub>H</sub>17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic T<sub>H</sub>17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys<sup>9</sup> (H3K9ac) of genes involved in aerobic glycolysis and T<sub>H</sub>17 pathogenic programs. In contrast, in nonpathogenic activin A–treated T<sub>H</sub>17 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<sub>H</sub>17 programs. Together, our findings uncover A<sub>2A</sub>R-AMPK signaling as a central metabolic checkpoint that suppresses T<sub>H</sub>17 cell pathogenicity.</div>\",\"PeriodicalId\":21658,\"journal\":{\"name\":\"Science Signaling\",\"volume\":\"18 905\",\"pages\":\"\"},\"PeriodicalIF\":6.6000,\"publicationDate\":\"2025-09-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Signaling\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scisignal.adr3177\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Signaling","FirstCategoryId":"99","ListUrlMain":"https://www.science.org/doi/10.1126/scisignal.adr3177","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Adenosine 2A receptor–dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming
Metabolic reprogramming controls protective and pathogenic T helper 17 (TH17) cell responses. When naïve T cells are differentiated into TH17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic TH17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A2A receptor (A2AR) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic TH17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic TH17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys9 (H3K9ac) of genes involved in aerobic glycolysis and TH17 pathogenic programs. In contrast, in nonpathogenic activin A–treated TH17 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 TH17 programs. Together, our findings uncover A2AR-AMPK signaling as a central metabolic checkpoint that suppresses TH17 cell pathogenicity.
期刊介绍:
"Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets.
The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment.
In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.