TRPM2 contributes to LPS/IFN纬-induced production of nitric oxide via the p38/JNK pathway in microglia

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• 作者：Takahito Miyake ; Hisashi Shirakawa ; Ayaka Kusano ; Shinya Sakimoto ; Masakazu Konno ; Takayuki Nakagawa ; Yasuo Mori ; Shuji Kaneko
• 关键词：TRP channel ; Ca2+ dynamics ; Microglia ; Nitric oxide ; MAPK ; LPS
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：7 February, 2014
• 年：2014
• 卷：444
• 期：2
• 页码：212-217
• 全文大小：1007 K

文摘

Microglia are immune cells that maintain brain homeostasis at a resting state by surveying the environment and engulfing debris. However, in some pathological conditions, microglia can produce neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO) that lead to neuronal degeneration. Inflammation-induced calcium (Ca²⁺) signaling is thought to underlie this abnormal activation of microglia, but the mechanisms are still obscure. We previously showed that combined application of lipopolysaccharide and interferon 纬 (LPS/IFN纬) induced-production of NO in microglia from wild-type (WT) mice is significantly reduced in microglia from transient receptor potential melastatin 2 (TRPM2)-knockout (KO) mice. Here, we found that LPS/IFN纬 produced a late-onset Ca²⁺ signaling in WT microglia, which was abolished by application of the NADPH oxidase inhibitor diphenylene iodonium (DPI) and ML-171. In addition, pharmacological blockade or gene deletion of TRPM2 channel in microglia did not show this Ca²⁺ signaling. Furthermore, pharmacological manipulation and Western blotting revealed that Ca²⁺ mobilization, the proline-rich tyrosine kinase 2 (Pyk2), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) contributed to TRPM2-mediated LPS/IFN纬-induced activation, while the extracellular signal-regulated protein kinase (ERK) did not. These results suggest that LPS/IFN纬 activates TRPM2-mediated Ca²⁺ signaling, which in turn increases downstream p38 MAPK and JNK signaling and results in increased NO production in microglia.