title: Glia-dependent TGF-beta signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis.
abstract: Autoimmune encephalomyelitis, a mouse model for multiple sclerosis, is characterized by the activation of immune cells, demyelination of axons in the CNS, and paralysis. We found that TGF-beta1 synthesis in glial cells and TGF-beta-induced signaling in the CNS were activated several days before the onset of paralysis in mice with autoimmune encephalomyelitis. While early production of TGF-beta1 was observed in glial cells TGF-beta signaling was activated in neurons and later in infiltrating T cells in inflammatory lesions. Systemic treatment with a pharmacological inhibitor of TGF-beta signaling ameliorated the paralytic disease and reduced the accumulation of pathogenic T cells and expression of IL-6 in the CNS. Priming of peripheral T cells was not altered, nor was the generation of TH17 cells, indicating that this effect was directed within the brain, yet affected the immune system. These results suggest that early production of TGF-beta1 in the CNS creates a permissive and dangerous environment for the initiation of autoimmune inflammation, providing a rare example of the brain modulating the immune system. Importantly, inhibition of TGF-beta signaling may have benefits in the treatment of the acute phase of autoimmune CNS inflammation.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305-5235, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ho
authors.forename: Marion S
authors.initials: MS
authors.lastname: Buckwalter
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hsu
authors.forename: Lowen Y
authors.initials: LY
authors.lastname: Lee
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D017930:Genes, Reporter; D006023:Glycoproteins / Q000008:administration & dosage / Q000276:immunology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009457:Neuroglia / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D053773:Transforming Growth Factor beta1; C445081:myelin oligodendrocyte glycoprotein (35-55)