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Japanese encephalitis is characterized by profound neuronal destruction/dysfunction and concomitant microgliosis/astrogliosis. Although substantial activation of glia is observed in Japanese encephalitis virus (JEV)-induced Japanese encephalitis, the inflammatory responses and consequences of astrocytes and microglial activation after JEV infection are not fully understood. In this study, infection of cultured neurons/glia with JEV caused neuronal death and glial activation, as evidenced by morphological transformation, increased cell proliferation and elevated tumour necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6 and RANTES (regulated upon activation, normal T-cell expressed and secreted) production. Replication-competent JEV caused all glial responses and neurotoxicity. However, replication-incompetent JEV lost these abilities, except for the ability to change microglial morphology. The bystander damage caused by activated glia also contributed to JEV-associated neurotoxicity. Microglia underwent morphological changes, increased cell proliferation and elevated TNF-a, IL-1b, IL-6 and RANTES expression in response to JEV infection. In contrast, IL-6 and RANTES expression, but no apparent morphological changes, proliferation or TNF-a/IL-1b expression, was demonstrated in JEV-infected astrocytes. Supernatants of JEV-infected microglia, but not JEV-infected astrocytes, induced glial activation and triggered neuronal death. Antibody neutralization studies revealed that TNF-a and IL-1b, but not RANTES or IL-6, released by activated microglia appeared to play roles in JEV-associated neurotoxicity. In conclusion, following JEV infection, neuronal death was accompanied by concomitant microgliosis and astrogliosis, and neurotoxic mediators released by JEV-activated microglia, rather than by JEV-activated astrocytes, had the ability to amplify the microglial response and cause neuronal death.

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The substantial activation of microglia in Japanese encephalitis virus (JEV)-induced Japanese encephalitis found in numerous studies demonstrates that the disease pathogenesis involves bystander damage caused by microglia-released mediators. Previously, we reported that microglia synthesized and secreted bioactive mediators with neurotoxic potential into the cultured supernatants in response to JEV infection. In this study, we found that the supernatants of JEV-infected microglia caused MK801-inhibitable neuronal damage in cultured neurons, indicating a potential excitotoxic mechanism. Infection with JEV was found to elicit the extracellular glutamate accumulation from microglia but not from neuron and astrocyte cultures. The glutaminase inhibitor 6-diazo-5-oxo-L-norleucine, cystine/glutamate antiporter inhibitor α-aminoadipic acid, and the gap junction inhibitor carbenoxolone reduced JEV infection-induced microglial glutamate release and neurotoxicity. We further demonstrated that tumor necrosis factor-alpha (TNF-α) was a key cytokine which stimulated extensive microglial glutamate release by up-regulating glutaminase expression via signals involving protein kinase C, cAMP responsive element-binding protein, and CAAT-enhancer-binding protein-beta. Although the elevated expression of excitatory amino acid transporter 1 and 2 was observed in JEV-infected cells, the glutamate uptake activity was significantly inhibited by TNF-α. The JEV infection-induced alterations, such as the extracellular glutamate release and glutamate-mediated excitoneurotoxicity, also occurred in neuron/glia cultures. Our findings support a potential link between neuroinflammation and the development of excitotoxic neuronal injury in Japanese encephalitis. The link between neuroinflammation and excitotoxic death may involve a mechanism in which TNF-α released by microglia plays a facilitory role in glutamate excitoneurotoxicity via up-regulation of glutamate synthesis and down-regulation of glutamate uptake.

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This study reports that highly oxygen-deficient CeO2 nanoparticles (NPs) can be obtained without reduction treatment by using thermal decomposition method. Different amounts of surfactants are used to control the size of the NPs. The X-ray absorption near-edge spectra (XANES) indicate that the concentration of Ce3+ is higher than 20% for all NPs. It is also found that most Ce3+ locates at the surface. Magnetic-measurement results show that room-temperature ferromagnetism (FM) of the CeO2 is closely related to the concentration of Ce3+ at the surface (I s Ce3+ ). Saturation magnetization (M s) reaches the maximum value with an I s Ce3+ of about 40%; however, M s decreases when I s Ce3+ is raised further. The highest M s in this study is obtained from the sample without surfactant (M s = 0.12 emu/g). This is comparable with the results in other reports in which the CeO2 NPs were subjected to the reduction treatment. Notably, NPs become paramagnetic when I s Ce3+ reaches 48%. This study suggests that oxygen vacancy is essential for the formation of FM in CeO2 NPs. However, FM will be suppressed with excess oxygen deficiency. The effect of surfactant on the growth and the stoichiometry of the CeO2 particles will also be discussed in this report.

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