Role of CD137L in peripheral nerve injury induced neuropathic pain

CD137L 在周围神经损伤引起的神经病理性疼痛中的作用

基本信息

批准号：
9483794
负责人：
Ling Cao
金额：
$ 33.19万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9483794
关键词：
Adult Affect Anti-inflammatory Antibodies Behavior Binding CD4 Positive T Lymphocytes Cell surface Cells Data Development Disease Equilibrium Exhibits Flow Cytometry Functional disorder Goals Hypersensitivity Immune Inflammatory Response Injury Interleukin-10 Interleukin-12 Investigation Knockout Mice Knowledge Lead Lesion Ligands Lumbar spinal cord structure Macrophage Activation Mediating Mediator of activation protein Microglia Monitor Multiple Sclerosis Mus Nerve Nerve Crush Nerve Regeneration Neuraxis Nociception Pain Pathogenesis Pathway interactions Peripheral Peripheral nerve injury Persistent pain Phase Phenotype Pilot Projects Play Production Property Quantitative Reverse Transcriptase PCR Recovery Recovery of Function Regimen Reporting Rodent Model Role Sensory Signal Transduction Spinal Cord Spinal nerve structure Sum Surface System TNF gene Testing Time United States Wild Type Mouse chronic pain cost cytokine effective therapy glial activation macrophage migration monocyte mouse model nerve injury neutralizing antibody novel pain model painful neuropathy preclinical study receptor response sciatic nerve somatosensory

项目摘要

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.

概括胶质细胞的激活和促炎介质的产生有助于神经病的发病机制疼痛。临床前研究表明小胶质细胞（中枢神经系统 (CNS) 的巨噬细胞）至关重要周围神经损伤引起的神经性疼痛发展中的早期调节因子。然而，其他研究表明，小胶质细胞的激活和各种促炎因子的产生在在神经损伤后的神经再生和功能恢复中发挥有益作用。此外，我们初步研究表明，与外周巨噬细胞类似，脊髓小胶质细胞表现出促炎作用脊髓神经后早期时间点的表型和后期时间点的抗炎表型 L5 横切（L5Tx，一种成熟的神经性疼痛小鼠模型）。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集。通过优化调节小胶质细胞的激活而不是完全抑制小胶质细胞的激活，我们可以潜在地限制小胶质细胞对神经性疼痛发展的贡献，同时保留小胶质细胞在神经再生中的有益特性。我们认为 CD137 配体 (CD137L) 在小胶质细胞表面表达，以促炎方式起作用，并且负调节 CD137L 可能会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，CD137L 的大多数已知功能都是从以下研究中获得的：外周免疫细胞。 CD137L 在中枢神经系统小胶质细胞中的作用尚未得到广泛研究，并且小胶质细胞 CD137L 在神经性疼痛发生中的作用尚不清楚。在本研究中，我们将确定小胶质细胞 CD137L 在周围神经损伤引起的神经病病理生理学中的作用通过检查两种小鼠神经性疼痛模型来观察疼痛。我们假设小胶质细胞 CD137L 参与周围神经损伤引起的疼痛样行为的发展负调节 CD137L 可以促进小胶质细胞活化向抗- 炎症状态，从而减少周围神经损伤引起的疼痛样行为。这个中央假设将通过三个具体目标进行检验：1）表征 CD137L 在外周血中的参与情况神经损伤引起的疼痛样行为。将在有和没有 CD137L 的小鼠中测试疼痛样行为表达。 2）评估周围神经损伤后脊髓小胶质细胞的激活状态与小胶质细胞 CD137L 表达的关系。小胶质细胞的激活将通过评估来监测通过流式细胞术检测小胶质细胞表型。 3) 确定 CD137 依赖性与 CD137- 的参与周围神经损伤诱导的、CD137L介导的疼痛样行为和小胶质细胞中的独立途径回应。总之，我们相信 CD137L 的研究可能会带来新的治疗方法显着减轻神经性疼痛，同时对神经恢复的不利影响最小。