Interferon-gamma receptor-mediated but not tumor necrosis factor receptor type 1- or type 2-mediated signaling is crucial for the activation of cerebral blood vessel endothelial cells and microglia in murine Toxoplasma encephalitis.
The regulatory role of interferon-gamma receptor (IFN-gammaR)- and tumor necrosis factor receptor (TNFR)-mediated immune reactions for the activation of cerebral endothelial cells, microglia, and astrocytes was evaluated in a model of murine Toxoplasma encephalitis (TE). Brain endothelial cells of wild-type mice reacted in response to Toxoplasma infection with a strong up-regulation of the vascular cell adhesion molecule, the intercellular adhesion molecule (ICAM)-1, and major histocompatibility complex (MHC) class I and II antigens. A similar response was seen in mice genetically deficient for either TNFR1, TNFR2, or both TNFRs, whereas IFN-gammaR-deficient (IFN-gammaR0/0) mice were found to be defective in the up-regulation of these molecules. However, recruitment of leukocytes to the brain and their intracerebral movement were not impaired in IFN-gammaR0/0 mice. In addition, microglia of Toxoplasma gondii-infected IFN-gammaR0/0 mice failed to induce expression of ICAM-1, leukocyte function-associated antigen (LFA)-1, and MHC class I and II antigens, whereas wild-type and TNFR-deficient mice up-regulated these molecules. Moreover, TNF-alpha mRNA production of F4/80(+) microglia/macrophages was impaired in IFN-gammaR0/0 mice, but not in TNFR-deficient mutants. However, induction of interleukin (IL)-1beta, IL-10, IL-12p40, and IL-15 mRNA was independent of IFN-gammaR and TNFR signaling. In conclusion, IFN-gammaR, but not TNFR signaling, is the major pathway for the activation of endothelial cells and microglia in murine TE. These findings differ from observations in other inflammatory central nervous system disorders, indicating specific regulatory mechanisms in this parasitic cerebral infection.
D000818:Animals; D001921:Brain / Q000098:blood supply; D004660:Encephalitis / Q000473:pathology / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D005260:Female; D007371:Interferon-gamma; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000502:physiology; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014124:Toxoplasmosis, Animal / Q000473:pathology / Q000503:physiopathology*; D016781:Toxoplasmosis, Cerebral / Q000473:pathology / Q000503:physiopathology*; D000096743:Interferon gamma Receptor