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 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 gp130fl/fl astrocytes was disturbed. Correspondingly, in vitro infected GFAP-Cre gp130fl/fl astrocytes inhibited the growth of T. gondii efficiently after stimulation with IFN-γ, 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.

Nitric oxide production increases during Toxoplasma gondii encephalitis in mice

“…Astrocytes are targeted by T. gondii in vitro (Fagard et al, 1999;Fischer et al, 1997), and in vivo studies have demonstrated that tachyzoites of T. gondii extensively infect astrocytes in the early period during cerebral invasion (Bjerkas, 1990;Gonzalez et al, 2007). Activated astrocytes perform an important regulatory role in TE by restricting lesions and preventing necrosis and parasite replication (Wilson and Hunter, 2004;Drögemüller et al, 2008;Stenzel et al, 2004). Studies have demonstrated the importance of GFAPpositive astrocytes in survival mechanisms in TE.…”

Glial reactivity in dogs with visceral leishmaniasis: correlation with T lymphocyte infiltration and with cerebrospinal fluid anti-Leishmania antibody titres

“…Streptavidin-biotin-peroxidase complex method. Bars 50 μm the negative aspects of reactive astrogliosis (Silver and Miller 2004), several studies of animal models describe the protective role of reactive astrogliosis within the CNS, such as the elimination of reactive oxygen species, BBB repair and the limitation of dissemination of inflammatory cells and infectious agents throughout the CNS (Bush et al 1999;Chen et al 2001;Drögemüller et al 2008;Faulkner et al 2004;Voskuhl et al 2009). …”

Glial regulation of the blood-brain barrier in health and disease

“…Severe reactive astrogliosis can result in the formation of a compact glial scar. Scar tissue is observed lining the borders of the site of CNS insult and is believed to act as a neuroprotective barrier to cells of the immune system and infectious agents [117][118][119][120].…”