The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation.
Activin Receptors, Type I
/ genetics
Activins
/ genetics
Animals
Cell Differentiation
Cells, Cultured
Encephalomyelitis, Autoimmune, Experimental
/ immunology
Humans
Mice
Mice, Knockout
Molecular Targeted Therapy
Multiple Sclerosis
/ immunology
Neurogenic Inflammation
/ immunology
Signal Transduction
Th17 Cells
/ immunology
Transforming Growth Factor beta
/ metabolism
ALK4
ALK5
Activin-A
EAE
ERK1/2
TGF-β1
autoimmune disease
multiple sclerosis
pathogenic Th17 cells
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
09 02 2021
09 02 2021
Historique:
received:
13
07
2020
revised:
12
10
2020
accepted:
16
12
2020
pubmed:
10
1
2021
medline:
8
9
2021
entrez:
9
1
2021
Statut:
ppublish
Résumé
Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.
Identifiants
pubmed: 33421362
pii: S1074-7613(20)30538-0
doi: 10.1016/j.immuni.2020.12.010
pmc: PMC7878438
mid: NIHMS1659077
pii:
doi:
Substances chimiques
Transforming Growth Factor beta
0
activin A
0
Activins
104625-48-1
Activin Receptors, Type I
EC 2.7.11.30
Acvr1b protein, mouse
EC 2.7.11.30
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
308-323.e6Subventions
Organisme : NIAID NIH HHS
ID : R01 AI123193
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI131238
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI160774
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
J Immunol. 2009 Aug 1;183(3):1715-23
pubmed: 19570828
Nat Rev Immunol. 2017 Sep;17(9):535-544
pubmed: 28555673
Cytokine Growth Factor Rev. 2013 Jun;24(3):285-95
pubmed: 23541927
Nat Immunol. 2007 Dec;8(12):1390-7
pubmed: 17994024
Science. 1994 Apr 1;264(5155):101-4
pubmed: 8140412
Immunity. 2019 Apr 16;50(4):924-940
pubmed: 30995507
Annu Rev Immunol. 2009;27:485-517
pubmed: 19132915
Nature. 2017 Nov 2;551(7678):105-109
pubmed: 29072299
Cell. 2014 Oct 9;159(2):440-55
pubmed: 25263330
Trends Endocrinol Metab. 2005 Mar;16(2):73-8
pubmed: 15734148
Cell. 2020 Jan 9;180(1):79-91.e16
pubmed: 31866067
Mol Cell Endocrinol. 2012 Aug 15;359(1-2):101-6
pubmed: 22037168
Nature. 2011 Jul 17;475(7357):514-8
pubmed: 21765430
Nat Rev Mol Cell Biol. 2018 Jul;19(7):419-435
pubmed: 29643418
Cell. 2006 Jul 28;126(2):375-87
pubmed: 16873067
Nat Immunol. 2012 Oct;13(10):991-9
pubmed: 22961052
Nature. 2006 May 11;441(7090):235-8
pubmed: 16648838
Cell Commun Signal. 2009 Jun 18;7:15
pubmed: 19538713
Immunity. 2006 Feb;24(2):179-89
pubmed: 16473830
Nat Rev Immunol. 2016 Nov 25;16(12):723-740
pubmed: 27885276
Mol Cancer. 2015 Oct 24;14:182
pubmed: 26497569
Cytokine Growth Factor Rev. 2009 Apr;20(2):153-64
pubmed: 19261538
Immunity. 2018 Apr 17;48(4):745-759.e6
pubmed: 29669252
Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12269-12280
pubmed: 32409602
Immunity. 2020 Feb 18;52(2):328-341.e5
pubmed: 32049050
Semin Immunopathol. 2013 Jul;35(4):481-99
pubmed: 23385857
Immunity. 2007 May;26(5):579-91
pubmed: 17481928
Eur J Endocrinol. 2001 Sep;145(3):225-36
pubmed: 11517001
Lancet Neurol. 2018 Feb;17(2):162-173
pubmed: 29275977
J Virol. 1996 Aug;70(8):5701-5
pubmed: 8764092
Trends Immunol. 2011 Sep;32(9):395-401
pubmed: 21782512
Sci Signal. 2019 Feb 26;12(570):
pubmed: 30808818
Eur J Immunol. 2013 Jul;43(7):1716-26
pubmed: 23620016
Nat Rev Immunol. 2007 Jun;7(6):443-53
pubmed: 17525753
J Cell Sci. 2005 Aug 15;118(Pt 16):3573-84
pubmed: 16105881
J Allergy Clin Immunol. 2012 Apr;129(4):1000-10.e3
pubmed: 22277204
Wiley Interdiscip Rev Dev Biol. 2013 Jan-Feb;2(1):47-63
pubmed: 23799630
Cold Spring Harb Perspect Biol. 2016 Aug 01;8(8):
pubmed: 27481709
Cell. 2006 Mar 24;124(6):1283-98
pubmed: 16564017
Cell. 2015 Dec 3;163(6):1400-12
pubmed: 26607794
Nat Rev Immunol. 2006 Apr;6(4):329-33
pubmed: 16557264
Nature. 2006 May 11;441(7090):231-4
pubmed: 16648837
Nat Immunol. 2018 Oct;19(10):1126-1136
pubmed: 30201991
Cell. 2015 Dec 3;163(6):1413-27
pubmed: 26607793
Cell Rep. 2018 Mar 6;22(10):2642-2653
pubmed: 29514093
J Immunol. 2006 Nov 15;177(10):6787-94
pubmed: 17082592
Immunity. 2019 Jul 16;51(1):77-89.e6
pubmed: 31229354
J Biol Chem. 2010 Sep 17;285(38):29039-43
pubmed: 20667820
J Autoimmun. 2019 Nov;104:102314
pubmed: 31416681
Immunity. 2011 Mar 25;34(3):396-408
pubmed: 21435587
J Exp Med. 2001 Sep 3;194(5):629-44
pubmed: 11535631
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10878-83
pubmed: 12949259
J Immunol. 2009 Apr 15;182(8):4633-40
pubmed: 19342638
Nature. 2010 Oct 21;467(7318):967-71
pubmed: 20962846
J Biol Chem. 2005 Jun 10;280(23):22115-23
pubmed: 15817471
Immunity. 2006 Jun;24(6):677-88
pubmed: 16782025
Cytokine Growth Factor Rev. 2006 Jun;17(3):157-71
pubmed: 16481210
Nat Immunol. 2016 Aug;17(8):976-84
pubmed: 27376469