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 |
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National Academy of Sciences
02-06-2020
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| Series: | From the Cover |
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| 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. |
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| AbstractList | 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
and
(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. 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. Pathogenic Th17 cells are critical drivers of autoimmune neuroinflammation in multiple sclerosis (MS). We report that administration of the cytokine activin-A ameliorated disease severity in an animal MS model and attenuated CNS neuroinflammation associated with decreased pathogenic Th17 responses. Whole-genome profiling and functional studies revealed that activin-A upregulated the antiinflammatory CD73 and CD39 ectonucleotidases and this was essential for the suppression of the pathogenic signature and encephalitogenic functions of Th17 cells. Mechanistically, activin-A signaling increased antiinflammatory gene expression through activation of the transcription factors AhR, STAT3, and c-Maf and inhibited pathogenic Th17 programs through down-regulation of the metabolic sensor, Hif1-α, and other inflammatory proteins. Of clinical relevance, we show that activin-A restrained pathogenic human Th17 cell responses in MS patients. 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. 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. |
| Author | Quintana, Francisco J. Wei, Ping Karageorgiou, Klinta Doskas, Triantafyllos Xanthou, Georgina Lomenick, Brett Pan, Fan Kalamatas, Themis Morianos, Ioannis Banos, Aggelos Trochoutsou, Aikaterini I. Manousopoulou, Antigoni Kapasa, Maria Belaidi, Elise Papadopoulou, Gina Sallusto, Federica Garbis, Spiros D. Semitekolou, Maria Konstantopoulos, Dimitris |
| Author_xml | – sequence: 1 givenname: Ioannis surname: Morianos fullname: Morianos, Ioannis – sequence: 2 givenname: Aikaterini I. surname: Trochoutsou fullname: Trochoutsou, Aikaterini I. – sequence: 3 givenname: Gina surname: Papadopoulou fullname: Papadopoulou, Gina – sequence: 4 givenname: Maria surname: Semitekolou fullname: Semitekolou, Maria – sequence: 5 givenname: Aggelos surname: Banos fullname: Banos, Aggelos – sequence: 6 givenname: Dimitris surname: Konstantopoulos fullname: Konstantopoulos, Dimitris – sequence: 7 givenname: Antigoni surname: Manousopoulou fullname: Manousopoulou, Antigoni – sequence: 8 givenname: Maria surname: Kapasa fullname: Kapasa, Maria – sequence: 9 givenname: Ping surname: Wei fullname: Wei, Ping – sequence: 10 givenname: Brett surname: Lomenick fullname: Lomenick, Brett – sequence: 11 givenname: Elise surname: Belaidi fullname: Belaidi, Elise – sequence: 12 givenname: Themis surname: Kalamatas fullname: Kalamatas, Themis – sequence: 13 givenname: Klinta surname: Karageorgiou fullname: Karageorgiou, Klinta – sequence: 14 givenname: Triantafyllos surname: Doskas fullname: Doskas, Triantafyllos – sequence: 15 givenname: Federica surname: Sallusto fullname: Sallusto, Federica – sequence: 16 givenname: Fan surname: Pan fullname: Pan, Fan – sequence: 17 givenname: Spiros D. surname: Garbis fullname: Garbis, Spiros D. – sequence: 18 givenname: Francisco J. surname: Quintana fullname: Quintana, Francisco J. – sequence: 19 givenname: Georgina surname: Xanthou fullname: Xanthou, Georgina |
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| Copyright | Copyright National Academy of Sciences Jun 2, 2020 Distributed under a Creative Commons Attribution 4.0 International License 2020 |
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| Keywords | autoimmune neuroinflammation activin-A cytokines ectonucleotidases Th17 cell differentiation |
| Language | English |
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| Notes | 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. |
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| Snippet | In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit... Pathogenic Th17 cells are critical drivers of autoimmune neuroinflammation in multiple sclerosis (MS). We report that administration of the cytokine activin-A... |
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| SubjectTerms | Activin Aromatic compounds Biological Sciences c-Maf protein CD73 antigen Cell activation Central nervous system Demyelination Experimental allergic encephalomyelitis Functionals Gene expression Genomes Helper cells Heterogeneity Hypoxia Hypoxia-inducible factor 1 Hypoxia-inducible factors In vivo methods and tests Inflammation Kinases Life Sciences Lymphocytes T Multiple sclerosis Pathogenicity Pathogens Receptors Stat3 protein Transcription |
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| Title | Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways |
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