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

• 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
• 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

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 神经胶质激活和促炎性介质的产生有助于神经性的发病机理 疼痛。临床前研究暗示小胶质细胞，即中枢神经系统（CNS）的巨噬细胞，是关键 外周神经损伤引起的神经性疼痛的早期调节剂。但是，其他 研究表明，小胶质激活和各种促炎性因子的产生 神经损伤后神经再生和功能恢复中的有益作用。而且，我们的初步 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 早期时间点的表型和脊柱神经后稍后时间点的抗炎表型 L5横断（L5TX，神经性疼痛的鼠模型）。我们建议这两个 小胶质激活状态对应于独特的小胶质细胞功能集。通过最佳调节 小胶质细胞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 保留小胶质细胞在神经再生中的有益特性。我们相信CD137配体 （CD137L）以小胶质表面表达的作用以促炎的方式作用，并对调节负面调节 CD137L可能会将活化小胶质细胞中的抗炎与抗炎平衡转移到抗抗炎 炎症状态。但是，CD137L的大多数已知功能是从有关的研究中获得的 外周免疫细胞。 CD137L在CNS小胶质细胞中的作用尚未进行广泛研究，并且 小胶质细胞CD137L在神经性疼痛发展中的作用尚不清楚。在这项研究中，我们将 确定小胶质细胞CD137L在周围神经损伤诱导的神经疗法的病理生理学中的作用 通过检查两种鼠神经性疼痛模型的疼痛。我们假设该小胶质细胞 CD137L参与周围神经损伤引起的疼痛样行为的发展，并 负面调节CD137L可以促进小胶质激活向抗 - 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 假设将通过三个特定目的进行检验：1）表征CD137L参与周围 神经损伤引起的疼痛样行为。有或没有CD137L的小鼠将测试类似疼痛的行为 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的表达有关。小胶质细胞的激活将通过评估来监测 小胶质表型通过流式细胞仪。 3）确定CD137依赖性与CD137-的参与 周围神经损伤引起的CD137L介导类似疼痛的行为和小胶质细胞的独立途径 回答。总而言之，我们认为对CD137L的研究可能会导致新的治疗方法 显着减轻神经性疼痛，而对神经恢复的不利影响最小。