热习服诱导的HSP60/TREM2在调节电磁辐射暴露的小胶质细胞M2型活化中的作用及机制研究

It has been reported that the electromagnetic fields(EMF) exposure could initiate the central neverous system(CNS) injury. But the machanism is not so clear and it is hard to prevent.In the three previous research projects supported by NSCF, we have proved that EMF stimulate M1 phenotype activation of microglia, which contributed to the CNS injury induced by EMF exposure. Our recently studies found that heat acclimation attenuates CNS injury, improve the functional recovery and modulate microglial M2 phenotype activation after EMF exposure. It has been proved that heat acclimation induce high expression of Hsp60. Moreover,Hsp60 is a ligand of TREM2 which is the key receptor trigger microglia activation. Based on these research results, we hypothesis that heat acclimation protect CNS against EMF exposure through modulate microglia M2 phenotype activation, which is switched on by HSP60/TREM2. We plan to study: (1)The relationship between activation and the neuroprotection induced by heat acclimation after EMF exposure. (2)The role of HSP60、TREM2 as the gateway in heat acclimation modulating the M2 phenotype activation of microglia stimulated by EMF. (3) The mechanism of PI3K/Akt signal transduction transer the signal of HSP60/TREM2 and regulate microglial M2 phenotype activation. This study could explore the cellular and molecular mechanism of the neuroprotect in heat acclimation attenuates CNS injury induced by EMF exposure, and provide a effective and feasible method to protect occupational population against EMF injury.

电磁辐射（EMF）具有中枢神经损伤效应，但机理不明，且难于有效防护。我们前期研究发现：热习服可减轻EMF中枢神经损伤效应，并可能与其调节小胶质细胞M2型活化有关。由于热习服可诱导大量HSP60产生，而HSP60又是调节小胶质细胞活化关键分子TREM2的配体。据此我们推测：热习服可能通过HSP60/TREM2及其信号通路调节小胶质细胞M2型活化，从而对EMF导致的中枢损伤产生保护作用。为进一步验证假设并探讨机理，本项目主要研究①热习服调节EMF刺激的小胶质细胞M2型活化与中枢神经保护作用之间的相关性；②HSP60、TREM2作为触发分子在热习服调节EMF刺激的小胶质细胞M2型活化中的关键作用；③HSP60/TREM2下游信号通路PI3K/Akt调节小胶质细胞M2型活化的机制。本项目不仅可揭示热习服对EMF中枢神经损伤保护作用的机制，而且有望为EMF暴露职业人群提供一条切实可行的有效防护措施。

电磁辐射环境污染对职业暴露人群中枢神经系统的危害正逐步被学者所认知。通过热习服对热耐受能力的提高，可明显减轻电磁辐射导致的学习记忆能力减退和中枢神经损伤，但内在作用机理尚不明了。本项目主要观察热习服后电磁辐射致中枢神经损伤的影响及小胶质细胞极性活化的变化，探讨了HSP60/TREM2 介导小胶质细胞 M2 型活化在热习服防护电磁辐射致中枢神经损伤中的作用和地位，并证实了通过抑制剂、siRNA或抗体干预HSP60、TREM2及其下游 PI3K/Akt 信号蛋白的表达，可以阻断热习服小胶质细胞 M2 型活化，部分消除了热习服对电磁辐射致中枢神经损伤的保护作用。应用在体动物和体外细胞模型，发现热习服可减轻电磁辐射小鼠行为功能、组织病理变化、神经元变性及凋亡等CNS损伤；热习服可调节电磁辐射小鼠和体外培养的小胶质细胞极性活化特性从损伤相关的促炎M1型活化向抗炎促修复的M2型活化的转变；应用抑制剂、siRNA干扰和抗体干预HSP60 、TREM2或通路蛋白，证实HSP60、TREM2在热习服调节电磁辐射刺激的小胶质细胞M2型活化中的作用；同时，发现热射病小鼠早期小胶质细胞促炎M1型活化和后期M2型活化，与具有明确热效应的电磁辐射暴露损伤中小胶质细胞持续性的促炎M1型活化略有不同。本项目研究结果丰富对小胶质细胞M2型活化机理的认识，为采用热习服调控小胶质细胞M1/M2活化表型来防护电磁辐射中枢神经损伤提供坚实的理论基础，而且为研发可定向调控小胶质细胞 M2 型活化的药物靶点提供明确线索。