title: Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation.
abstract: Astrocytes are activated in experimental autoimmune encephalomyelitis (EAE) and have been suggested to either aggravate or ameliorate EAE. However, the mechanisms leading to an adverse or protective effect of astrocytes on the course of EAE are incompletely understood. To gain insight into the astrocyte-specific function of gp130 in EAE, we immunized mice lacking cell surface expression of gp130, the signal-transducing receptor for cytokines of the IL-6 family, with myelin oligodendrocyte glycoprotein(35-55) peptide. These glial fibrillary acid protein (GFAP)-Cre gp130(fl/fl) mice developed clinically a significantly more severe EAE than control mice and succumbed to chronic EAE. Loss of astrocytic gp130 expression resulted in apoptosis of astrocytes in inflammatory lesions of GFAP-Cre gp130(fl/fl) mice, whereas gp130(fl/fl) control mice developed astrogliosis. Astrocyte loss of GFAP-Cre gp130(fl/fl) mice was paralleled by significantly larger areas of demyelination and significantly increased numbers of CD4 T cells in the CNS. Additionally, loss of astrocytes in GFAP-Cre gp130(fl/fl) mice resulted in a reduction of CNS regulatory Foxp3(+) CD4 T cells and an increase of IL-17-, IFN-γ-, and TNF-producing CD4 as well as IFN-γ- and TNF-producing CD8 T cells, illustrating that astrocytes regulate the phenotypic composition of T cells. An analysis of mice deficient in either astrocytic gp130- Src homology region 2 domain-containing phosphatase 2/Ras/ERK or gp130-STAT1/3 signaling revealed that prevention of astrocyte apoptosis, restriction of demyelination, and T cell infiltration were dependent on the astrocytic gp130-Src homology region 2 domain-containing phosphatase 2/Ras/ERK, but not on the gp130-STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE.
authors.affiliation: Institut für Medizinische Mikrobiologie, Otto-von-Guericke-Universität Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Fahad
authors.initials: F
authors.lastname: Haroon
authors.forename: Katrin
authors.initials: K
authors.lastname: Drögemüller
authors.forename: Ulrike
authors.initials: U
authors.lastname: Händel
authors.forename: Anna
authors.initials: A
authors.lastname: Brunn
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
authors.forename: Gopala
authors.initials: G
authors.lastname: Nishanth
authors.forename: Werner
authors.initials: W
authors.lastname: Mueller
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: Martina
authors.initials: M
authors.lastname: Deckert
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D018631:ras Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; C494200:Il6st protein, mouse; C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D050822:Cytokine Receptor gp130; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins