Role of CD137L in peripheral nerve injury induced neuropathic pain

总结 胶质细胞活化和促炎介质的产生参与神经病理性损伤的发病机制 痛苦临床前研究表明，小胶质细胞，即中枢神经系统（CNS）的巨噬细胞， 外周神经损伤诱导的神经病理性疼痛发展中的早期调节因子。但其他 研究表明，小胶质细胞的激活和各种促炎因子的产生起着重要的作用。 在神经损伤后的神经再生和功能恢复中的有益作用。此外，我们的初步 研究表明，类似于外周巨噬细胞，脊髓小胶质细胞表现出促炎性， 在脊髓神经损伤后的早期时间点具有抗炎表型和在随后的时间点具有抗炎表型 L5横断（L5 Tx，一种成熟的神经性疼痛鼠模型）。我们建议这两个 小胶质细胞激活状态对应于独特的小胶质细胞功能组。通过优化调节 小胶质细胞活化，而不是完全抑制小胶质细胞的活化，我们可以潜在地 限制小胶质细胞对神经性疼痛的发展的贡献，同时 保留小胶质细胞在神经再生中的有益特性。我们认为CD 137配体 在小胶质细胞表面表达的CD 137 L以促炎方式起作用， CD 137 L可以潜在地将激活的小胶质细胞中的促炎与抗炎平衡转向抗炎。 炎症状态然而，CD 137 L的大多数已知功能是从以下研究中获得的： 外周免疫细胞CD 137 L在CNS小胶质细胞中的作用尚未得到广泛研究， 小胶质细胞CD 137 L在神经病理性疼痛发生中的作用尚不清楚。在这项研究中，我们将 确定小胶质细胞CD 137 L在周围神经损伤诱导的神经病理性 疼痛通过检查两个小鼠模型的神经性疼痛。我们假设小胶质细胞 CD 137 L参与外周神经损伤诱导的疼痛样行为的发展， 负性调节CD 137 L可以促进小胶质细胞活化向抗CD 137 L转移。 炎症状态，从而减少外周神经损伤诱导疼痛样行为。这次中央 将通过三个具体目标来检验假设：1）表征外周血中CD 137 L的参与， 神经损伤引起的疼痛样行为。将在具有和不具有CD 137 L的小鼠中测试疼痛样行为 表情2)周围神经损伤后脊髓小胶质细胞活化状态的研究 与小胶质细胞CD 137 L的表达有关。将通过评估来监测小胶质细胞活化 通过流式细胞术检测小胶质细胞表型。和3）确定CD 137依赖性与CD 137-依赖性的参与。 外周神经损伤诱导的、CD 137 L介导的痛样行为和小胶质细胞中的独立通路 应答总之，我们相信对CD 137 L的研究可能会导致新的治疗方法， 同时对神经恢复具有最小的不利影响。

Summary Glial activation and production of proinflammatory mediators contribute to the pathogenesis of neuropathic pain. Pre-clinical studies implicate microglia, the macrophages of the central nervous system (CNS), as critical early regulators in the development of peripheral nerve injury-induced neuropathic pain. However, other studies indicate that microglial activation and the production of various proinflammatory factors play a beneficial role in nerve regeneration and functional recovery following nerve injury. Moreover, our preliminary studies show that similar to peripheral macrophages, spinal cord microglia exhibit a proinflammatory phenotype at early time points and an anti-inflammatory phenotype at later time points following spinal nerve L5 transection (L5Tx, a well-established murine model of neuropathic pain). We propose that these two microglial activation states correspond to unique sets of microglial functions. By optimally regulating microglial activation rather than completely inhibiting the activation of microglia, we can potentially limit the contribution of microglia to the development of neuropathic pain while simultaneously preserving the beneficial properties of microglia in nerve regeneration. We believe that CD137 ligand (CD137L) expressed on microglial surface acts in a proinflammatory manner and that negatively modulating CD137L can potentially shift the pro- vs. anti-inflammatory balance in activated microglia towards an anti- inflammatory state. However, most of the known functions of CD137L have been obtained from studies on peripheral immune cells. The role of CD137L in CNS microglia has not been studied extensively and the role of microglial CD137L in the development of neuropathic pain is unknown. In this study, we will determine the role of microglial CD137L in the pathophysiology of peripheral nerve injury-induced neuropathic pain through the examination of two murine models of neuropathic pain. We hypothesize that microglial CD137L is involved in the development of peripheral nerve injury -induced pain-like behaviors and that negatively modulating CD137L can promote a shift in microglial activation towards an anti- inflammatory state and thus reduce peripheral nerve injury-induced pain-like behaviors. This central hypothesis will be tested via three specific aims: 1) Characterize the involvement of CD137L in peripheral nerve injury-induced pain-like behaviors. Pain-like behaviors will be tested in mice with and without CD137L expression. 2) Evaluate the activation status of spinal cord microglia following peripheral nerve injury in relation to the expression of microglial CD137L. Microglial activation will be monitored through assessing microglial phenotype via flow cytometry. And 3) determine the involvement of CD137-dependent vs. CD137- independent pathways in peripheral nerve injury-induced, CD137L-mediated pain-like behaviors and microglial responses. In sum, we believe that the investigation of CD137L could lead to novel treatment that could significantly reduce neuropathic pain while has minimal adverse impact on nerve recovery.