PPAR-γ/ABCA1信号对富髓鞘巨噬细胞功能及脊髓损伤的调控作用研究

Macrophages play a critical role in the pathogenesis of spinal cord injury by regulating inflammatory response and secondary injury. Our preliminary data indicate that infiltrating macrophages greatly phagocytose myelin debris resulted from demyelination and subsequently become myelin-laden macrophages. The accumulated myelin debris in these cells induces adverse effects such as M1-like polarization, production of pro-inflammatory cytokines and neurotoxicity. However, how to restore the normal function of macrophages remains unsolved. Based on excessive lipid accumulation in myelin-laden macrophages, we hypothesize that promoting lipid efflux may inhibit the adverse effects of myelin-laden macrophages and further ameliorate spinal cord injury. This project aims to examine the potential role of PPAR-γ/ABCA1 signaling in regulating the function of myelin-laden macrophages, and evaluate the protective effect of ABCA1 overexpression on spinal cord injury. By focusing on the beneficial effect of macrophage lipid efflux on spinal cord injury, this project may help us to better understand the macrophage-related pathogenesis of inflammatory response and provide potential therapeutic targets for spinal cord injury.

巨噬细胞在脊髓损伤的发病进程中起到重要作用，它广泛参与了损伤后炎症反应的发生和继发性损伤的形成。我们既往的研究表明，脊髓损伤后，由血液浸润的巨噬细胞将大量吞噬脱髓鞘产生的髓鞘碎片，进而形成富髓鞘巨噬细胞。髓鞘碎片在巨噬细胞内的长期过量积累，导致其产生炎症反应、神经细胞毒性等有害作用，然而目前尚无有效调控手段。由于富髓鞘巨噬细胞内积累了大量脂质，我们假设：刺激富髓鞘巨噬细胞的脂质外排，可能抑制其有害作用，进而减轻脊髓损伤程度。本项目将：1）检验激活PPAR-γ/ABCA1脂质外排信号通路对富髓鞘巨噬细胞功能的调控作用；2）运用ABCA1转基因小鼠研究过表达ABCA1对脊髓损伤的保护作用。本项目拟从巨噬细胞脂质外排角度探索新的脊髓损伤保护策略，其成果有助于为脊髓损伤的治疗提供新的理论依据和药物靶点。

巨噬细胞在脊髓损伤发病进程中起到重要作用，它广泛参与了损伤后炎症反应的发生和继发性损伤的形成。我们既往研究结果表明脊髓损伤后由血液浸润的巨噬细胞将大量吞噬脱髓鞘产生的髓鞘碎片，进而形成富髓鞘巨噬细胞。髓鞘碎片在巨噬细胞内的长期过量积累，导致了炎症反应、神经细胞毒性等有害作用，然而目前尚无有效调控手段。据此，我们设想刺激富髓鞘巨噬细胞外排脂质可能抑制上述病理性改变，进而减轻脊髓损伤程度。脂联素是一种由脂肪组织分泌的具有调节炎症状态的重要激素。本研究探讨了脂联素信号通路在脊髓损伤后巨噬细胞介导的神经炎症中的作用和相关机制。实验数据显示利用脂联素拟似物AdipoRon激活脂联素受体能体外抑制髓鞘巨噬细胞的髓磷脂脂质积累，并通过APPL1/PPARγ/LXRα/ABCA1介导脂质外流来减轻炎症、恢复细胞正常功能。与之类似，体内数据证实脊髓损伤后静脉注射AdipoRon可抑制巨噬细胞聚集，减少髓鞘脂质积累，继而降低脊髓损伤后组织损伤和星形胶质细胞增生，最终维持了运动功能。我们的研究揭示了脊髓损伤背景下脂联素与巨噬细胞之间的功能联系，提示通过脂联素信号通路激活促进巨噬细胞脂质外排可以减轻髓鞘巨噬细胞介导的神经炎症，因此可能成为一种潜在治疗脊髓损伤的新手段。