Tang Sung-Chun, Arumugam Thiruma V, Xu Xiangru, Cheng Aiwu, Mughal Mohamed R, Jo Dong Gyu, Lathia Justin D, Siler Dominic A, Chigurupati Srinivasulu, Ouyang Xin, Magnus Tim, Camandola Simonetta, Mattson Mark P
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA.
Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13798-803. doi: 10.1073/pnas.0702553104. Epub 2007 Aug 10.
The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-gamma stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death.
固有免疫系统通过Toll样受体（TLR）感知病原微生物的入侵和组织损伤，这一机制曾被认为仅限于免疫细胞。我们现在报告，神经元表达多种TLR，并且在受到γ干扰素刺激和能量剥夺时，神经元中TLR2和TLR4的水平会升高。来自TLR2基因敲除小鼠和TLR4突变小鼠的神经元对能量剥夺诱导的细胞死亡具有抗性，这与涉及Jun N末端激酶和转录因子AP-1的促凋亡信号级联反应的激活减少有关。响应于缺血/再灌注损伤，大脑皮质神经元中TLR2和TLR4的表达增加，与野生型对照小鼠相比，TLR2或TLR4缺陷小鼠中风引起的脑损伤量和神经功能缺损明显更少。我们的研究结果确立了神经元中TLR2和TLR4的促凋亡信号通路，这可能使它们易受缺血性死亡的影响。
