TY - JOUR
T1 - Astrocyte gp130 expression is critical for the control of Toxoplasma encephalitis
AU - Drögemüller, Katrin
AU - Helmuth, Ulrike
AU - Brunn, Anna
AU - Sakowicz-Burkiewicz, Monika
AU - Gutmann, David H.
AU - Mueller, Werner
AU - Deckert, Martina
AU - Schlüter, Dirk
PY - 2008/8/15
Y1 - 2008/8/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=52949085996&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.181.4.2683
DO - 10.4049/jimmunol.181.4.2683
M3 - Article
C2 - 18684959
AN - SCOPUS:52949085996
SN - 0022-1767
VL - 181
SP - 2683
EP - 2693
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -