Gp130-dependent astrocytic survival is critical for the control of autoimmune central nervous system inflammation

Fahad Haroon, Katrin Drögemüller, Ulrike Händel, Anna Brunn, Dirk Reinhold, Gopala Nishanth, Werner Mueller, Christian Trautwein, Matthias Ernst, Martina Deckert, Dirk Schlüter

    Research output: Contribution to journalArticlepeer-review

    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 glycoprotein35-55 peptide. These glial fibrillary acid protein (GFAP)-Cre gp130fl/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 gp130fl/fl control mice developed astrogliosis. Astrocyte loss of GFAP-Cre gp130fl/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 gp130fl/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 domaincontaining phosphatase 2/Ras/ERK, but not on the gp130-STAT1/3 pathway, further demonstrating that gp130-dependent astrocyte activation is crucial to ameliorate EAE. Copyright © 2011 by The American Association of Immunologists, Inc.
    Original languageEnglish
    Pages (from-to)6521-6531
    Number of pages10
    JournalJournal of Immunology
    Volume186
    Issue number11
    DOIs
    Publication statusPublished - 1 Jun 2011

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