Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways
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 pathogenic...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 22; pp. 12269 - 12280 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
National Academy of Sciences
02-06-2020
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| Series: | From the Cover |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | 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. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: I.M., G.P., M.S., F.S., F.P., F.J.Q., and G.X. designed research; I.M., A.I.T., G.P., M.S., A.B., A.M., P.W., and B.L. performed research; E.B. contributed new reagents/analytic tools; T.K., K.K., and T.D. recruited patients and acquired clinical samples; I.M., A.I.T., G.P., M.S., D.K., A.M., M.K., P.W., S.D.G., and G.X. analyzed data; and I.M., S.D.G., F.J.Q., and G.X. wrote the paper. 1A.I.T. and G.P. contributed equally to this work. Edited by Gabriel A. Rabinovich, University of Buenos Aires, Autonomous City of Buenos Aires, Argentina, and approved April 1, 2020 (received for review October 24, 2019) 2S.D.G. and F.J.Q. contributed equally to this work. |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1918196117 |