Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines
Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines
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DOI：
10.1523/jneurosci.4268-04.2005
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发表时间：
2005-02-16
影响因子：
5.3
通讯作者：
Herkenham, M
中科院分区：
文献类型：
--
作者：
Chakravarty, S;Herkenham, M
炎性激动剂如脂多糖（LPS）在外周给药后诱导强烈的全身以及CNS反应。先天免疫系统的反应需要触发Toll样受体4（TLR4），但CNS后遗症的起源一直存在争议。我们证明了TLR4转录本在小鼠脑中的脑膜、脑室室管膜、脑室周围器官、沿着血管和实质小胶质细胞中的表达。使用嵌合体小鼠检查CNS驻留细胞与造血细胞中表达的TLR 4对CNS炎症发展的贡献。野生型和TLR4突变小鼠之间的相互骨髓嵌合体表明，CNS驻留细胞上的TLR4是全身性LPS给药后脑中持续炎症所必需的。造血TLR4单独支持急性期细胞因子的全身释放，但CNS中促炎基因的转录在持续时间上减少。相比之下，TLR4在抗辐射细胞中的功能足以促进嵌合小鼠脑中的炎症进展，尽管血清中细胞因子明显缺乏。令人惊讶的是，血清皮质酮的暂时上升也依赖于非造血细胞中的TLR4信号传导。我们的研究结果表明，持续的CNS特异性炎症和内毒素血症期间皮质酮升高需要CNS驻留细胞中的TLR4功能，而不依赖于全身性细胞因子效应。
Inflammatory agonists such as lipopolysaccharide (LPS) induce robust systemic as well as CNS responses after peripheral administration. Responses in the innate immune system require triggering of toll-like receptor 4 (TLR4), but the origin of CNS sequelas has been controversial. We demonstrate expression of TLR4 transcripts in mouse brain in the meninges, ventricular ependyma, circumventricular organs, along the vasculature, and in parenchymal microglia. The contribution of TLR4 expressed in CNS resident versus hematopoietic cells to the development of CNS inflammation was examined using chimeric mice. Reciprocal bone marrow chimeras between wild-type and TLR4 mutant mice show that TLR4 on CNS resident cells is critically required for sustained inflammation in the brain after systemic LPS administration. Hematopoietic TLR4 alone supported the systemic release of acute phase cytokines, but transcription of proinflammatory genes in the CNS was reduced in duration. In contrast, TLR4 function in radiation-resistant cells was sufficient for inflammatory progression in the brains of chimeric mice, despite the striking absence of cytokine elevations in serum. Surprisingly, a temporal rise in serum corticosterone was also dependent on TLR4 signaling in nonhematopoietic cells. Our findings demonstrate a requirement for TLR4 function in CNS-resident cells, independent of systemic cytokine effects, for sustained CNS-specific inflammation and corticosterone rise during endotoxemia.