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TNF-α acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection.

Hayasaka D, Shirai K, Aoki K, Nagata N, Simantini DS, Kitaura K, Takamatsu Y, Gould E, Suzuki R, Morita K - PLoS ONE (2013)

Bottom Line: Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease.Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease.In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Institute of Tropical Medicine, GCOE program, Leading Graduate School Program, Nagasaki University, Nagasaki, Nagasaki, Japan. hayasaka@nagasaki-u.ac.jp

ABSTRACT
Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

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Neuronal degeneration and inflammation in the brains of TNF-α KO mice infected with JaOArS982.(A and B) Histopathological features of WT (A) and TNF-α KO (B) mice infected with 104 pfu of JaOArS982 at 10 days pi. JEV antigens were detected using E-protein specific JEV antibody (insets). Each experiment represents six and five mice of WT and TNF-α KO, respectively. Inflammatory reactions and neuronal degeneration were seen in the WT mice. The TNFa KO mice showed acute necrotic changes in the brain cortex. (C) Number of infiltrating leukocytes, T cells (CD3+), CD4+ T cells, CD8+ T cells, B cells (CD19+), NK cells (NK1.1+) and macrophages including microglia (F4/80+) in brains of WT (mock: n=5, Day 10: n=6) and TNF-α KO (mock: n=5, Day 10: n=7). p: Mann Whitney test.
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pone-0071643-g006: Neuronal degeneration and inflammation in the brains of TNF-α KO mice infected with JaOArS982.(A and B) Histopathological features of WT (A) and TNF-α KO (B) mice infected with 104 pfu of JaOArS982 at 10 days pi. JEV antigens were detected using E-protein specific JEV antibody (insets). Each experiment represents six and five mice of WT and TNF-α KO, respectively. Inflammatory reactions and neuronal degeneration were seen in the WT mice. The TNFa KO mice showed acute necrotic changes in the brain cortex. (C) Number of infiltrating leukocytes, T cells (CD3+), CD4+ T cells, CD8+ T cells, B cells (CD19+), NK cells (NK1.1+) and macrophages including microglia (F4/80+) in brains of WT (mock: n=5, Day 10: n=6) and TNF-α KO (mock: n=5, Day 10: n=7). p: Mann Whitney test.

Mentions: Histopathological examination of TNF-α KO mice revealed severe neuronal loss in extensive areas of brain cortex when compared with WT mice (Figure 6A and B). However, the proportion of infiltrated cells involving leukocytes (CD45), T cells (CD3, CD4 or CD8), B cells (CD19), NK cells (NK1.1) and macrophages (F4/80) did not appear to differ significantly between TNF-α KO and WT mice (Figure 6C). These observations suggest that the increased levels of cytokines in TNF-α KO mice were due to qualitative differences of their expression in inflammatory cells, rather than quantitative increases of infiltrating cytokine producing cells.


TNF-α acts as an immunoregulator in the mouse brain by reducing the incidence of severe disease following Japanese encephalitis virus infection.

Hayasaka D, Shirai K, Aoki K, Nagata N, Simantini DS, Kitaura K, Takamatsu Y, Gould E, Suzuki R, Morita K - PLoS ONE (2013)

Neuronal degeneration and inflammation in the brains of TNF-α KO mice infected with JaOArS982.(A and B) Histopathological features of WT (A) and TNF-α KO (B) mice infected with 104 pfu of JaOArS982 at 10 days pi. JEV antigens were detected using E-protein specific JEV antibody (insets). Each experiment represents six and five mice of WT and TNF-α KO, respectively. Inflammatory reactions and neuronal degeneration were seen in the WT mice. The TNFa KO mice showed acute necrotic changes in the brain cortex. (C) Number of infiltrating leukocytes, T cells (CD3+), CD4+ T cells, CD8+ T cells, B cells (CD19+), NK cells (NK1.1+) and macrophages including microglia (F4/80+) in brains of WT (mock: n=5, Day 10: n=6) and TNF-α KO (mock: n=5, Day 10: n=7). p: Mann Whitney test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3733918&req=5

pone-0071643-g006: Neuronal degeneration and inflammation in the brains of TNF-α KO mice infected with JaOArS982.(A and B) Histopathological features of WT (A) and TNF-α KO (B) mice infected with 104 pfu of JaOArS982 at 10 days pi. JEV antigens were detected using E-protein specific JEV antibody (insets). Each experiment represents six and five mice of WT and TNF-α KO, respectively. Inflammatory reactions and neuronal degeneration were seen in the WT mice. The TNFa KO mice showed acute necrotic changes in the brain cortex. (C) Number of infiltrating leukocytes, T cells (CD3+), CD4+ T cells, CD8+ T cells, B cells (CD19+), NK cells (NK1.1+) and macrophages including microglia (F4/80+) in brains of WT (mock: n=5, Day 10: n=6) and TNF-α KO (mock: n=5, Day 10: n=7). p: Mann Whitney test.
Mentions: Histopathological examination of TNF-α KO mice revealed severe neuronal loss in extensive areas of brain cortex when compared with WT mice (Figure 6A and B). However, the proportion of infiltrated cells involving leukocytes (CD45), T cells (CD3, CD4 or CD8), B cells (CD19), NK cells (NK1.1) and macrophages (F4/80) did not appear to differ significantly between TNF-α KO and WT mice (Figure 6C). These observations suggest that the increased levels of cytokines in TNF-α KO mice were due to qualitative differences of their expression in inflammatory cells, rather than quantitative increases of infiltrating cytokine producing cells.

Bottom Line: Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease.Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease.In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Institute of Tropical Medicine, GCOE program, Leading Graduate School Program, Nagasaki University, Nagasaki, Nagasaki, Japan. hayasaka@nagasaki-u.ac.jp

ABSTRACT
Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

Show MeSH
Related in: MedlinePlus