{"doi":"10.1073/pnas.1918196117","title":"Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways","abstract":"In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A–induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.","journal":"Proceedings of the National Academy of Sciences","year":2020,"id":94246,"datarank":0.5495342469194471,"base_score":3.6635616461296463,"endowment":3.6635616461296463,"self_citation_contribution":0.5495342469194471,"citation_network_contribution":0.0,"self_endowment_contribution":0.5495342469194471,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":470612,"name":"Aikaterini Trochoutsou","orcid":null,"position":1,"is_corresponding":false},{"id":469731,"name":"Gina Papadopoulou","orcid":"0000-0002-3022-4350","position":2,"is_corresponding":false},{"id":469732,"name":"Maria Semitekolou","orcid":"0000-0002-0318-6774","position":3,"is_corresponding":false},{"id":469733,"name":"Aggelos Banos","orcid":"0000-0002-5647-6505","position":4,"is_corresponding":false},{"id":469734,"name":"Dimitris Konstantopoulos","orcid":"0000-0003-2142-3021","position":5,"is_corresponding":false},{"id":344104,"name":"Antigoni Manousopoulou","orcid":"0000-0001-5028-1865","position":6,"is_corresponding":false},{"id":470613,"name":"Μαρία Καπασά","orcid":null,"position":7,"is_corresponding":false},{"id":469735,"name":"Ping Wei","orcid":"0000-0002-2742-719X","position":8,"is_corresponding":false},{"id":469736,"name":"Brett Lomenick","orcid":"0000-0002-5023-9998","position":9,"is_corresponding":false},{"id":469737,"name":"Elise Belaïdi","orcid":"0000-0003-4589-1612","position":10,"is_corresponding":false},{"id":470614,"name":"T. Kalamatas","orcid":null,"position":11,"is_corresponding":false},{"id":470615,"name":"Klinta Karageorgiou","orcid":null,"position":12,"is_corresponding":false},{"id":470616,"name":"Triantafyllos Doskas","orcid":null,"position":13,"is_corresponding":false},{"id":73799,"name":"Federica Sallusto","orcid":"0000-0003-3750-2752","position":14,"is_corresponding":false},{"id":107271,"name":"Fan Pan","orcid":"0000-0002-4187-5095","position":15,"is_corresponding":false},{"id":344107,"name":"Spiros D. Garbis","orcid":"0000-0002-1050-0805","position":16,"is_corresponding":false},{"id":18937,"name":"Francisco J. Quintana","orcid":"0000-0001-8156-0736","position":17,"is_corresponding":false},{"id":469738,"name":"Georgina Xanthou","orcid":"0000-0001-7944-2343","position":18,"is_corresponding":false},{"id":469730,"name":"Ioannis Morianos","orcid":"0000-0001-5207-0869","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T22:32:04.778261Z","pmid":"32409602","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}