PMID- 33421362 OWN - NLM STAT- MEDLINE DCOM- 20210907 LR - 20220210 IS - 1097-4180 (Electronic) IS - 1074-7613 (Print) IS - 1074-7613 (Linking) VI - 54 IP - 2 DP - 2021 Feb 9 TI - The TGF-beta superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation. PG - 308-323.e6 LID - S1074-7613(20)30538-0 [pii] LID - 10.1016/j.immuni.2020.12.010 [doi] AB - Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor beta1 (TGF-beta1) 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-beta superfamily member closely related to TGF-beta1, 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-beta1-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. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Wu, Bing AU - Wu B AD - Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Zhang, Song AU - Zhang S AD - Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Guo, Zengli AU - Guo Z AD - Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Bi, Yanmin AU - Bi Y AD - Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Zhou, Mingxia AU - Zhou M AD - Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Li, Ping AU - Li P AD - Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. FAU - Seyedsadr, Maryamsadat AU - Seyedsadr M AD - Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA. FAU - Xu, Xiaojiang AU - Xu X AD - Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. FAU - Li, Jian-Liang AU - Li JL AD - Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. FAU - Markovic-Plese, Silva AU - Markovic-Plese S AD - Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA. FAU - Wan, Yisong Y AU - Wan YY AD - Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: wany@email.unc.edu. LA - eng GR - R01 AI123193/AI/NIAID NIH HHS/United States GR - R01 AI131238/AI/NIAID NIH HHS/United States GR - R01 AI160774/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20210108 PL - United States TA - Immunity JT - Immunity JID - 9432918 RN - 0 (Transforming Growth Factor beta) RN - 0 (activin A) RN - 104625-48-1 (Activins) RN - EC 2.7.11.30 (Activin Receptors, Type I) RN - EC 2.7.11.30 (Acvr1b protein, mouse) SB - IM MH - Activin Receptors, Type I/genetics/metabolism MH - Activins/genetics/*metabolism MH - Animals MH - Cell Differentiation MH - Cells, Cultured MH - Encephalomyelitis, Autoimmune, Experimental/*immunology MH - Humans MH - Mice MH - Mice, Knockout MH - Molecular Targeted Therapy MH - Multiple Sclerosis/*immunology MH - Neurogenic Inflammation/*immunology MH - Signal Transduction MH - Th17 Cells/*immunology MH - Transforming Growth Factor beta/*metabolism PMC - PMC7878438 MID - NIHMS1659077 OTO - NOTNLM OT - ALK4 OT - ALK5 OT - Activin-A OT - EAE OT - ERK1/2 OT - TGF-beta1 OT - autoimmune disease OT - multiple sclerosis OT - pathogenic Th17 cells COIS- Declaration of interests The authors declare no competing interests. EDAT- 2021/01/10 06:00 MHDA- 2021/09/08 06:00 PMCR- 2022/02/09 CRDT- 2021/01/09 20:07 PHST- 2020/07/13 00:00 [received] PHST- 2020/10/12 00:00 [revised] PHST- 2020/12/16 00:00 [accepted] PHST- 2021/01/10 06:00 [pubmed] PHST- 2021/09/08 06:00 [medline] PHST- 2021/01/09 20:07 [entrez] PHST- 2022/02/09 00:00 [pmc-release] AID - S1074-7613(20)30538-0 [pii] AID - 10.1016/j.immuni.2020.12.010 [doi] PST - ppublish SO - Immunity. 2021 Feb 9;54(2):308-323.e6. doi: 10.1016/j.immuni.2020.12.010. Epub 2021 Jan 8.