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Published June 2, 2020 | Supplemental Material + Erratum + Published
Journal Article Open

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.

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.

Attached Files

Published - 12269.full.pdf

Supplemental Material - pnas.1918196117.sapp.pdf

Erratum - 17447.full.pdf

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Created:
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