Double-stranded RNA stimulates chemokine expression in microglia through vacuolar pH-dependent activation of intracellular signaling pathways
Double-stranded RNA stimulates chemokine expression in microglia through vacuolar pH-dependent activation of intracellular signaling pathways
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DOI：
10.1111/j.1471-4159.2005.03354.x
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发表时间：
2005-10-01
影响因子：
4.7
通讯作者：
Kurane, I
中科院分区：
文献类型：
--
作者：
Nakamichi, K;Saiki, M;Kurane, I
在嗜神经病毒感染期间，小胶质细胞作为趋化因子的来源，从而调节外周血白细胞的募集和中枢神经系统内的多细胞免疫反应。在此，我们对小胶质细胞对双链RNA(DsRNA)产生趋化因子的反应进行了全面的研究，双链RNA是病毒感染的一种保守的分子模式。趋化因子基因转录分析显示，dsRNA可强烈诱导小胶质细胞表达CXC趋化因子配体10(CXCL10)和CC趋化因子配体5(CCL5)。我们还观察到dsRNA刺激触发了核因子-kappa B(NF-kappa B)和丝裂原活化蛋白激酶(MAPK)介导的信号通路的激活，包括细胞外信号调节激酶1和2(ERK1/2)、p38和c-Jun氨基末端激酶(JNK)。小胶质细胞CXCL10对dsRNA的反应是通过NF-kappa B、p38和JNK途径诱导的，而dsRNA诱导的CCL5的产生依赖于JNK，而不依赖于所测试的其他信号转导分子。此外，细胞内小泡的酸性环境是激活细胞信号对dsRNA的反应所必需的。综上所述，这些结果表明，dsRNA结构的识别选择性地诱导了小胶质细胞中CXCL10和CCL5的反应，其方式是通过空泡pH依赖的NF-kappa B和MAPK信号通路的激活。
During neurotropic virus infection, microglia act as a source of chemokines, thereby regulating the recruitment of peripheral leukocytes and the multicellular immune response within the CNS. Herein, we present a comprehensive study on the chemokine production by microglia in response to double-stranded RNA (dsRNA), a conserved molecular pattern of virus infection. Transcriptional analyses of chemokine genes revealed that dsRNA strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. We also observed that the dsRNA stimulation triggered the activation of signaling pathways mediated by nuclear factor kappa B (NF-kappa B) and mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK). The microglial CXCL10 response to dsRNA was induced via NF-kappa B, p38, and JNK pathways, whereas the dsRNA-induced CCL5 production was dependent on JNK, but not on the other signal-transducing molecules tested. In addition, the acidic environment of intracellular vesicles was required for the activation of cellular signaling in response to dsRNA. Taken together, these results suggest that the recognition of dsRNA structure selectively induces the CXCL10 and CCL5 responses in microglia through vacuolar pH-dependent activation of NF-kappa B and MAPK signaling pathways.