Sarm1信号通路在创伤性损伤诱导神经元天然免疫反应中的功能和分子机制

Our research group has recently observed that upon the traumatic injuries to their axons, neuronal cells could rapidly express a collection of chemokines and cytokines. Importantly, this immune response reflects the intrinsic innate immunity of neurons, as it doesn't depend on the presence of immune cells or other non-neuronal cells. Moreover, we have found that Sarm1, a Myd88-homolog adaptor protein, is specifically expressed in neurons and exerts a key role in the traumatic injury-induced neuronal innate immunity. Little had been known about the neuronal immune response to traumatic injuries in the past, and our research has begun to uncover this novel form of innate immunity as well as its underlying molecular mechanism. Based on our existing results, this project is aimed to understand the function and signaling mechanism of Sarm1 pathway in the neuronal innate immune response to traumatic injuries. The research work will be focused on the following specific aims: (1) Sarm1 in the neuronal innate immunity and its signaling mechanism; (2) Jnk kinases in the neuronal innate immunity and their signaling mechanism; (3) c-Jun transcription factor in the neuronal innate immunity and its molecular mechanism. This research project will significantly broaden our knowledge on mammalian innate immunity, and at the same time, promote the in-depth understanding of the mechanisms regulating inflammation in the nervous systems.

申请人课题组的最新研究发现，神经元在其轴突创伤性损伤后能够迅速表达多种趋化因子和细胞因子。值得注意的是，这一现象是神经元内在的免疫反应能力，而不依赖于免疫细胞或其他非神经元细胞。不仅如此，神经元特异性表达的Myd88同源蛋白Sarm1在其中起到重要的调控功能。领域内以往研究对于创伤性损伤诱导的神经元天然免疫反应极少报道，而申请人课题组的最新工作开始揭示这一全新的天然免疫反应类型及其分子信号机制。基于已有研究基础，本申请项目将着重探索Sarm1信号通路在创伤性损伤诱导神经元天然免疫反应中的功能和分子机制，研究工作将围绕以下三个部分展开：1、Sarm1在神经元天然免疫反应中的功能及分子机制；2、Jnk激酶在神经元天然免疫反应中的功能及分子机制；3、转录因子c-Jun在神经元天然免疫反应中的功能及分子机制。项目研究成果将拓展对于天然免疫反应的全面认识，并推动对于神经系统炎症反应机制的深入理解。

创伤性损伤可引发炎症反应，导致严重的神经病理学后果。然而，与免疫细胞或神经胶质细胞不同，神经元对创伤性损伤的免疫能力仍有待充分研究。在这项研究中，我们发现神经元可以自主地检测到远端的轴突损伤，从而快速产生一系列特定的细胞因子和趋化因子。这种神经元免疫反应在空间和时间上与损伤诱导的轴突退行分开进行。我们进一步通过遗传筛选确定这种免疫反应受TIR结构域接头蛋白Sarm1/Myd88-5调节。同时，本研究表明Sarm1通过下游Jnk-c-Jun信号发挥作用。并且，阻断该Sarm1-Jnk-c-Jun通路，能有效地阻遏免疫细胞向受损伤的神经组织的募集。通过本项目研究，我们发现了Sarm1神经元天然免疫反应的重要功能和信号转导机制。