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Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways

Morianos, Ioannis and Trochoutsou, Aikaterini I. and Papadopoulou, Gina and Semitekolou, Maria and Banos, Aggelos and Konstantopoulos, Dimitris and Manousopoulou, Antigoni and Kapasa, Maria and Wei, Ping and Lomenick, Brett and Belaidi, Elise and Kalamatas, Themis and Karageorgiou, Klinta and Doskas, Triantafyllos and Sallusto, Federica and Pan, Fan and Garbis, Spiros D. and Quintana, Francisco J. and Xanthou, Georgina (2020) Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways. Proceedings of the National Academy of Sciences of the United States of America, 117 (22). pp. 12269-12280. ISSN 0027-8424. PMCID PMC7275751. https://resolver.caltech.edu/CaltechAUTHORS:20200515-103106365

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1918196117DOIArticle
https://www.pnas.org/content/suppl/2020/05/13/1918196117.DCSupplementalPublisherSupporting Information
https://doi.org/10.1073/pnas.2008491117DOIRelated Article: Time to activin on pathogenic T cells - May 22, 2020
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7275751/PubMed CentralArticle
https://doi.org/10.1073/pnas.2012449117DOICorrection
ORCID:
AuthorORCID
Trochoutsou, Aikaterini I.0000-0002-2956-2221
Papadopoulou, Gina0000-0002-3022-4350
Banos, Aggelos0000-0002-5647-6505
Konstantopoulos, Dimitris0000-0003-2142-3021
Manousopoulou, Antigoni0000-0001-5028-1865
Belaidi, Elise0000-0003-4589-1612
Garbis, Spiros D.0000-0002-1050-0805
Xanthou, Georgina0000-0001-7944-2343
Additional Information:© 2200 National Academy of Sciences. Published under the PNAS license. 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). First published May 14, 2020. We thank A. Apostolidou for assistance with flow cytometry and sorting; A. Agapaki and S. Psarras for histology preparations; and Eleni Rigana and Stamatis Pagakis for assistance with the confocal microscopy imaging. 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. A.I.T. and G.P. contributed equally to this work. S.D.G. and F.J.Q. contributed equally to this work. The authors declare no competing interest. This article is a PNAS Direct Submission. Data deposition: The RNA-seq reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE146439). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (dataset identifier PXD017757). This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1918196117/-/DCSupplemental.
Errata:The authors note that an additional affiliation should be listed for Federica Sallusto. The new affiliation should appear as Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland. The corrected author and affiliation lines appear below. The online version has been corrected.
Subject Keywords:cytokines; autoimmune neuroinflammation; Th17 cell differentiation; ectonucleotidases; activin-A
Issue or Number:22
PubMed Central ID:PMC7275751
Record Number:CaltechAUTHORS:20200515-103106365
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200515-103106365
Official Citation:Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways. Ioannis Morianos, Aikaterini I. Trochoutsou, Gina Papadopoulou, Maria Semitekolou, Aggelos Banos, Dimitris Konstantopoulos, Antigoni Manousopoulou, Maria Kapasa, Ping Wei, Brett Lomenick, Elise Belaidi, Themis Kalamatas, Klinta Karageorgiou, Triantafyllos Doskas, Federica Sallusto, Fan Pan, Spiros D. Garbis, Francisco J. Quintana, Georgina Xanthou. Proceedings of the National Academy of Sciences Jun 2020, 117 (22) 12269-12280; DOI: 10.1073/pnas.1918196117
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103230
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 May 2020 17:43
Last Modified:22 Jul 2020 18:48

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