title: Astrocyte gp130 expression is critical for the control of Toxoplasma encephalitis.
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 gp130(fl/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 gp130(fl/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 gp130(fl/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-gamma and the IFN-gamma-induced GTPase (IGTP), which mediate parasite control in astrocytes, was even increased in GFAP-Cre gp130(fl/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 gp130(fl/fl) astrocytes inhibited the growth of T. gondii efficiently after stimulation with IFN-gamma, whereas neighboring noninfected and TNF-stimulated GFAP-Cre gp130(fl/fl) astrocytes became apoptotic. Collectively, these are the first experiments demonstrating a crucial function of astrocytes in CNS infection.
authors.affiliation: Institut für Medizinische Mikrobiologie, Otto-von-Guericke-Universität, Magdeburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Drögemüller
authors.forename: Ulrike
authors.initials: U
authors.lastname: Helmuth
authors.forename: Anna
authors.initials: A
authors.lastname: Brunn
authors.forename: Monika
authors.initials: M
authors.lastname: Sakowicz-Burkiewicz
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Werner
authors.initials: W
authors.lastname: Mueller
authors.forename: Martina
authors.initials: M
authors.lastname: Deckert
authors.forename: Dirk
authors.initials: D
authors.lastname: Schlüter
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016781:Toxoplasmosis, Cerebral / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; C494200:Il6st protein, mouse; D008024:Ligands; D009419:Nerve Tissue Proteins; C528900:glial fibrillary astrocytic protein, mouse; D050822:Cytokine Receptor gp130