Astrocyte gp130 expression is critical for the control of Toxoplasma encephalitis

Katrin Drögemüller, Ulrike Helmuth, Anna Brunn, Monika Sakowicz-Burkiewicz, David H. Gutmann, Werner Mueller, Martina Deckert, Dirk Schlüter

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Toxoplasma gondii infects astrocytes, neurons and microglia cells in the CNS and, after acute encephalitis, persists within neurons. Robust astrocyte activation is a hallmark of Toxoplasma encephalitis (TE); however, the in vivo function of astrocytes is largely unknown. To study their role in TE we generated C57BL/6 GFAP-Cre gp130fl/fl mice (where GFAP is glial fibrillary acid protein), which lack gp130, the signal-transducing receptor for IL-6 family cytokines, in their astrocytes. In the TE of wild-type mice, the gp130 ligands IL-6, IL-11, IL-27, LIF, oncostatin M, ciliary neurotrophic factor, B cell stimulating factor, and cardiotrophin-1 were up-regulated. In addition, GFAP+ astrocytes of gp130fl/fl control mice were activated, increased in number, and efficiently restricted inflammatory lesions and parasites, thereby contributing to survival from TE. In contrast, T. gondii- infected GFAP-Cre gp130fl/fl mice lost GFAP+ astrocytes in inflammatory lesions resulting in an inefficient containment of inflammatory lesions, impaired parasite control, and, ultimately, a lethal necrotizing TE. Production of IFN-γ and the IFN-γ-induced GTPase (IGTP), which mediate parasite control in astrocytes, was even increased in GFAP-Cre gp130fl/fl mice, indicating that instead of the direct antiparasitic effect the immunoregulatory function of GFAP-Cre gp130 fl/fl astrocytes was disturbed. Correspondingly, in vitro infected GFAP-Cre gp130fl/fl astrocytes inhibited the growth of T. gondii efficiently after stimulation with IFN-β, whereas neighboring noninfected and TNF-stimulated GFAP-Cre gp130fl/fl astrocytes became apoptotic. Collectively, these are the first experiments demonstrating a crucial function of astrocytes in CNS infection.

Original languageEnglish
Pages (from-to)2683-2693
Number of pages11
JournalJournal of Immunology
Volume181
Issue number4
DOIs
StatePublished - Aug 15 2008

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