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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy
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The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy

机译：Toll样受体4的中枢神经系统在先天神经免疫和疼痛性神经病中的作用

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Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. This study demonstrates for the first time, to our knowledge, a critical role for CNS innate immunity by means of microglial Toll-like receptor 4 (TLR4) in the induction phase of behavioral hypersensitivity in a mouse and rat model of neuropathy. We hypothesized that after L5 nerve transection, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. To test this hypothesis, experiments were undertaken to assess tactile and thermal hypersensitivity in genetically altered (i.e., TLR4 knockout and point-mutant) mice after L5 nerve transection. In a complementary study, TLR4 antisense oligodeoxynucleotide (ODN) was administered intrathecally to L5 spinal nerve injured rats to reduce the expression of spinal TLR4. Both the genetically altered mice and the rats treated with TLR4 antisense ODN displayed significantly attenuated behavioral hypersensitivity and decreased expression of spinal microglial markers and proinflammatory cytokines as compared with their respective control groups. This finding shows that TLR4 contributes to the initiation of CNS neuroimmune activation after L5 nerve transection. Further understanding of this early, specific, innate CNS/microglial response and how it leads to sustained glialeuronal hypersensitivity may point to new therapies for the prevention and treatment of neuropathic pain syndromes.
机译：由于我们对其发病机理的不完全了解，神经性疼痛仍然是普遍存在且持续存在的临床问题。据我们所知，这项研究首次证明了通过小胶质Toll样受体4（TLR4）在中枢神经系统疾病小鼠和大鼠行为超敏反应的诱导阶段中枢神经系统先天免疫的关键作用。我们假设L5神经横断后，刺激小胶质细胞膜结合的TLR4触发中枢神经系统神经免疫激活和随后的细胞因子表达。为了检验该假设，进行了实验以评估L5神经横断后的基因改变（即TLR4基因敲除和点突变）小鼠的触觉和热超敏反应。在一项补充研究中，对L5脊髓神经损伤的大鼠鞘内施用TLR4反义寡聚脱氧核苷酸（ODN），以降低脊髓TLR4的表达。与各自的对照组相比，转基因小鼠和接受TLR4反义ODN治疗的大鼠均表现出明显的行为超敏性减弱，脊髓小胶质细胞标记物和促炎细胞因子的表达降低。该发现表明TLR4有助于L5神经横断后CNS神经免疫激活的启动。对这种早期，特异性，先天的中枢神经系统/小胶质细胞反应及其如何导致持续的神经胶质/神经元超敏反应的进一步理解，可能为预防和治疗神经性疼痛综合征提供了新的疗法。

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