Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation
Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation
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DOI：
10.1523/jneurosci.3567-08.2009
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发表时间：
2009-02-18
影响因子：
5.3
通讯作者：
Swain, Mark G.
中科院分区：
文献类型：
--
作者：
D'Mello, Charlotte;Le, Tai;Swain, Mark G.
在中枢神经系统外发生的炎症性疾病中，外周和大脑之间通过体液和/或神经途径的交流导致中枢神经的改变和相关的行为改变。我们最近发现了另一种在器官中心外周炎症的情况下免疫到中枢神经系统的通信途径：即免疫细胞进入大脑。在我们目前的研究中，使用小鼠炎症性肝损伤模型，我们已经证实了肝脏炎症小鼠中活化单核细胞显著浸润到大脑中，并确定了介导这种单核细胞运输的机制。具体来说，我们发现在肝脏炎症存在的情况下，小鼠表现出升高的脑单核细胞化学吸引蛋白(MCP)-1水平，以及循环中表达ccr2的单核细胞数量增加。在缺乏MCP-1/CCL2或CCR2的炎症小鼠中，大脑单核细胞的募集被取消。此外，在肝脏炎症小鼠中，在单核细胞浸润前，小胶质细胞被激活并产生MCP-1/CCL2。此外，需要外周肿瘤坏死因子(TNF) α信号来刺激小胶质细胞产生MCP-1/CCL2。通过TNF受体1 （TNFR1）的TNF α信号传导是这些观察到的效果所必需的，因为在TNFR1缺陷小鼠的肝脏炎症中，MCP-1/CCL2的小胶质表达和脑单核细胞募集都被显著抑制，而在TNFR2缺陷小鼠中没有抑制。我们的研究结果表明，在外周器官为中心的炎症中存在一种新的免疫到中枢神经系统的通讯途径，这可能对发生在中枢神经系统外的许多炎症性疾病中常见的脑神经传递改变的发展具有特定的意义。
In inflammatory diseases occurring outside the CNS, communication between the periphery and the brain via humoral and/or neural routes results in central neural changes and associated behavioral alterations. We have recently identified another immune-to-CNS communication pathway in the setting of organ-centered peripheral inflammation: namely, the entrance of immune cells into the brain. In our current study, using a mouse model of inflammatory liver injury, we have confirmed the significant infiltration of activated monocytes into the brain in mice with hepatic inflammation and have defined the mechanism that mediates this trafficking of monocytes. Specifically, we show that in the presence of hepatic inflammation, mice demonstrate elevated cerebral monocyte chemoattractant protein (MCP)-1 levels, as well as increased numbers of circulating CCR2-expressing monocytes. Cerebral recruitment of monocytes was abolished in inflamed mice that lacked MCP-1/CCL2 or CCR2. Furthermore, in mice with hepatic inflammation, microglia were activated and produced MCP-1/CCL2 before cerebral monocyte infiltration. Moreover, peripheral tumor necrosis factor (TNF)alpha signaling was required to stimulate microglia to produce MCP-1/CCL2. TNF alpha signaling via TNF receptor 1 (TNFR1) is required for these observed effects since in TNFR1 deficient mice with hepatic inflammation, microglial expression of MCP-1/CCL2 and cerebral monocyte recruitment were both markedly inhibited, whereas there was no inhibition in TNFR2 deficient mice. Our results identify the existence of a novel immune-to-CNS communication pathway occurring in the setting of peripheral organ-centered inflammation which may have specific implications for the development of alterations in cerebral neurotransmission commonly encountered in numerous inflammatory diseases occurring outside the CNS.