Neuronal gp130 expression is crucial to prevent neuronal loss, hyperinflammation, and lethal course of murine Toxoplasma encephalitis.
The obligate intracellular parasite Toxoplasma gondii infects and persists within neurons of approximately one-third of the human population. Intracerebral control of T. gondii largely depends on interferon (IFN)-γ-producing T cells, which induce antiparasitic effector mechanisms in infected cells, as well as immunosuppressive cytokines, which prevent immunopathology. To gain further insight into the role of neurons in Toxoplasma encephalitis (TE), we generated C57BL/6 synapsin-I (Syn)-Cre gp130(fl/fl) mice, which lack gp130, the signal-transducing receptor for the IL-6 family of cytokines, in their neurons. On infection with T. gondii, Syn-Cre gp130(fl/fl) mice failed to control T. gondii infection and died of necrotizing TE before day 77. In contrast, gp130(fl/fl) control mice efficiently restricted parasite replication and survived the infection. TE in Syn-Cre gp130(fl/fl) mice was characterized by a hyperinflammatory immune response with increased numbers of IL-17- and IFN-γ-producing CD4 and CD8 T cells but reduced intracerebral production of immunosuppressive transforming growth factor (TGF)-β and IL-27. Additional in vitro experiments found that IL-6 stimulation of neurons induced gp130-dependent TGF-β1, TGF-β2, and IL-27 production. Importantly, gp130 expression and stimulation with IL-6 cytokine family members also reduced death and apoptosis of infected cultured neurons. Correspondingly, TE in Syn-Cre gp130(fl/fl) but not gp130(fl/fl) mice was characterized by progressive neuronal loss. Collectively, these findings indicate a crucial protective function of gp130-expressing neurons in a model of chronic encephalitis.
Institute of Medical Microbiology, Otto-von-Guericke University, Magdeburg, Magdeburg, Germany.
Ulrike
U
Händel
Anna
A
Brunn
Katrin
K
Drögemüller
Werner
W
Müller
Martina
M
Deckert
Dirk
D
Schlüter
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000469:parasitology; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D004660:Encephalitis / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000276:immunology* / Q000473:pathology; D016019:Survival Analysis; D014122:Toxoplasma / Q000302:isolation & purification; D016781:Toxoplasmosis, Cerebral / Q000276:immunology* / Q000469:parasitology / Q000473:pathology
D016207:Cytokines; C494200:Il6st protein, mouse; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D050822:Cytokine Receptor gp130