Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α-dependent pathways.
5'-Nucleotidase
/ metabolism
Activins
/ pharmacology
Animals
Antigens, CD
/ metabolism
Apyrase
/ metabolism
Cell Differentiation
Encephalomyelitis, Autoimmune, Experimental
/ drug therapy
GPI-Linked Proteins
/ metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Inflammation
/ immunology
Mice
Mice, Inbred C57BL
Multiple Sclerosis
/ drug therapy
Th17 Cells
/ immunology
Th17 cell differentiation
activin-A
autoimmune neuroinflammation
cytokines
ectonucleotidases
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
02 06 2020
02 06 2020
Historique:
pubmed:
16
5
2020
medline:
19
8
2020
entrez:
16
5
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 32409602
pii: 1918196117
doi: 10.1073/pnas.1918196117
pmc: PMC7275751
doi:
Substances chimiques
Antigens, CD
0
GPI-Linked Proteins
0
HIF1A protein, human
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
activin A
0
Activins
104625-48-1
5'-Nucleotidase
EC 3.1.3.5
NT5E protein, human
EC 3.1.3.5
Apyrase
EC 3.6.1.5
CD39 antigen
EC 3.6.1.5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
12269-12280Subventions
Organisme : NINDS NIH HHS
ID : R01 NS102807
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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