Impaired resistance to the development of toxoplasmic encephalitis in interleukin-6-deficient mice

Abstract

The role of interleukin-6 (IL-6) in the pathogenesis of toxoplasmic encephalitis (TE) was examined by using IL-6-targeted mutant (IL-6 ؊/؊) mice. At 4 and 8 weeks after infection with the ME49 strain of Toxoplasma gondii, significantly greater numbers of T. gondii cysts and areas of inflammation associated with tachyzoites were observed in brains of IL-6 ؊/؊ mice than in those of control mice. Large areas of necrosis were observed only in brains of IL-6 ؊/؊ mice. Tachyzoites were frequently detected in the areas of necrosis, suggesting that necrosis was caused by proliferation of the parasite. These results indicate that IL-6 is protective against development of TE by preventing formation of T. gondii cysts and proliferation of tachyzoites in brains of infected mice. Whereas in brains of control mice, large numbers of inflammatory cells were always observed in areas where tachyzoites were detected, in brains of IL-6 ؊/؊ mice, only small numbers of inflammatory cells were observed in many areas with tachyzoites. Lymphocyte preparations isolated from brains of infected control mice had significantly higher ratios of ␥/␦ T cells and CD4 ؉ ␣/␤ T cells but lower ratios of CD8 ؉ ␣/␤ T cells compared to those of infected IL-6 ؊/؊ mice. There were no differences in the ratios of these T-cell subsets in spleens between these mice. The amounts of mRNA for gamma interferon (IFN-␥) detected by reverse transcriptase PCR were significantly smaller in brains of IL-6 ؊/؊ mice than in those of control mice, whereas amounts of IL-10 mRNA were greater in the former than in the latter. IL-6 mRNA was detected only in infected control mice. The protective activity of IL-6 against development of TE appears to be through its ability to stimulate IFN-␥ production and induce infiltration and accumulation of different T-cell subsets in brains of infected mice.

Astroglia in Sepsis Associated Encephalopathy

“…During T. gondii infection astrocytic cytokines can directly target invading pathogens. For instance, IL-6 and IFN-γ reduce parasite burden, whereas animals with deleted gp130 (IL-6 receptor) in astrocytes show rapidly progressive lethal necrotising encephalitis [129,166,169,170]. The IFN-γ similarly inhibits parasite replication in astrocytes.…”

Astrocytes: Integrative Regulators of Neuroinflammation in Stroke and Other Neurological Diseases

“…For example, IL-1β is thought to damage neurons in epilepsy directly [146], while TGF-β is neuroprotective in stroke [131,147] and its signaling is required in neurons to promote survival [148]. Similarly, IFN-γ and IL-6 have been shown to reduce the parasite burden, as well as activate immune cells during Toxoplasma infection [149,150]. In this case, since immune cell activation commonly leads to reducing the parasite burden, it can become difficult to determine which effects of astrocytic cytokines control the immune response, and which alter it by affecting the parasite burden directly.…”

VCAM-1/α4β1 Integrin Interaction Is Crucial for Prompt Recruitment of Immune T Cells into the Brain during the Early Stage of Reactivation of Chronic Infection with Toxoplasma gondii To Prevent Toxoplasmic Encephalitis

“…Three days after discontinuation of sulfadiazine treatment, anesthetized animals were perfused intracardially with PBS to remove intravascular leukocytes. Mononuclear cells were isolated from brains from each group as described previously (30). After treating the cells with anti-Fc␥II/III receptor MAb, the cells were incubated for 30 min with a PE-conjugated MAb to CD4 (clone RM4-5) or a FITC-conjugated MAb to CD8␤ (clone 53-6.7) in combination with peridinin chlorophyll protein (PerCP)-conjugated MAb to CD3ε (clone 145-2C11).…”