TREM2通过CSF1R/DAP12信号通路调控小胶质细胞功能介导急性痛转化为慢性痛的机制研究

Chronic pain is mainly caused by acute pain, but the exact mechanism is unclear. Our study with others suggests that microglia activation plays an important role in this transformation. Therefore, exploring the molecular mechanism of microglia activation will provide a new target for analgesia. Our latest study reported that microglia played a key role in the transition from acute to chronic pain. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified innate immune receptor only expressed on microglia in central nervous system. The first symptoms of the deficiency of TREM2 or its adaptor receptor DAP12 in humans appear in early adulthood as pain and tenderness, mostly in the ankles and feet. The precise role of TREM2 during chronic pain has not been fully understood. Our preliminary experiments showed that, compared with wild-type (C57BL/6) mice, inflammatory pain and pathological pain in the early phase were more sensitive in TREM2-/- mice. After TREM2 knockout, the activation and proliferation of microglia and the upregulation of CSF1R in spinal cord were exacerbated following spared nerve injury, but microglial phagocytosis was reduced. Also, astrocyte was early activated. According to the key role of CSF1R/DAP12 in microglial activation and hypersensitivity, we propose that TREM2 might be critical in microglial function and the onset of chronic pain. In the project, we will clarify the role of TREM2 in the transition from acute to chronic pain, and further explore the molecular mechanism and biological function of TREM2 in regulating the function of microglia and astrocyte. The founding will validate the application of a therapeutic strategy aimed at TREM2 or CSF1R/DAP12 activation as a promising approach to tackle microglial activation and provide a new molecule target for pain therapy.

慢性痛主要由急性痛转化而来，但目前机制不清。我们和他人的研究表明，小胶质细胞激活在这一转化中起重要作用。因此探究小胶质细胞活化的分子机制将为镇痛提供新的靶点。髓样细胞触发受体2（TREM2）在中枢神经系统中仅表达在小胶质细胞。人TREM2或其接头受体DAP12基因突变引起的第一症状是成年早期出现脚踝自发痛和压痛。但TREM2在慢性痛中的作用尚不清楚。我们发现TREM2敲除小鼠对炎性痛和神经病理性疼痛早期反应更敏感，小胶质细胞激活增殖和集落细胞刺激因子（CSFR1）上调显著，但吞噬能力降低；星形胶质细胞早期激活也明显。因CSF1R/DAP12激活导致小胶质细胞活化和痛敏，我们推测TREM2下调经CSF1R/DAP12通路激活小胶质细胞介导疼痛的慢性化。本项目将明确TREM2在急性痛转化为慢性痛中的作用，并深入探讨其调控小胶质细胞及星形胶质细胞功能的分子机制，为治疗慢性痛提供新的理论和靶点。

慢性痛主要由急性痛转化而来，但目前机制不清。我们和他人的研究表明，小胶质细胞激活在这一转化中起重要作用。因此探究小胶质细胞活化的分子机制将为镇痛提供新的靶点。髓样细胞触发受体2（TREM2）在中枢神经系统中仅表达在小胶质细胞中。人TREM2或其接头受体DAP 12基因突变引起Nasu-Hakola病（NHD），也称为多囊性脂膜性骨发育不良伴硬化性白质脑病（PLOS），其第一症状是成年早期出现脚踝自发痛和压痛 但TREM2在慢性痛中的作用尚不清楚。我们发现TREM2 KO小鼠对炎性痛反应更敏感而且神经元激活更显著，且小胶质细胞激活明显。而鞘内敲除TREM2可加重炎症性疼痛，但脊髓内过表达TREM2可减轻炎症性疼痛。此外，体内或体外阻断TREM2可引起机械异常疼痛和小胶质细胞炎性反应。表明TREM2能负向调控小胶细胞激活。接着我们发现，TREM2敲除导致外周神经损伤疼痛更敏感、小胶质细胞激活程度、突触前末梢蛋白以及细胞外基质（ECM）相互作用增多。进一步的在体与体外实验显示这是由于TREM2 KO后CSF1引起的小胶质细胞炎症反应加剧以及促进损伤终末的吞噬以及新终末的生长所致。接着我们发现这与CSF1R通路敏感以及Galectin-3合成增多有关。与之前研究显示TREM2促进脑内小胶质细胞吞噬和炎症不同，TREM2在脊髓中是抑制小胶质细胞的吞噬和炎症，并揭示这一负向调控小胶质细胞功能是通过抑制CSF1R/Galectin-3信号通路影响脊髓背角神经元信息以及调控小胶质细胞吞噬和细胞外基质（ECM）形成修饰影响痛觉神经环路，从而介导疼痛的慢性化。本项目将明确TREM2在急性痛转化为慢性痛中的作用，并深入探讨其调控小胶质细胞及星形胶质细胞功能的分子机制，为治疗慢性痛提供新的理论和靶点。

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