ADAMs介导小胶质细胞TREM2受体构型转化在放射性脑损伤中的机制研究

Head and neck cancer is one of the common malignant tumors and radiotherapy is the primary treatment. Yet about 15% of the patients complicated with brain injury after radiotherapy. Our previous data indicated that the impairment of microglia phagocytosis impedeing remyelination and axon regeneration, however the mechanism is unknown. TREM2 is the major myelin phagocytic receptor on the microglia, which exists in both transmembrane and soluble secretory forms. The transmembrane associated type functions as a scavenger receptor, while soluble secretory type (sTREM2) mediates microglia inflammatory responses. The ADAMs family are involved in “ectodomain shedding” of TREM2, which are major proteases that mediate the conversion of TREM2 from transmembrane-associated form to secreted form. However, how to precisely target and regulate ADAMs subtype to promote myelin phagocytosis remains to be further studied. This study aims to explore the change of myelin phagocytic receptor TREM2 after irradiation and to optimize the phagocytosis of microglia through precise regulation on ADAMs-TREM2 pathway. The change of sTREM2 level in patients’ biological samples will also be detected. This study would provide evidence of targeting microglia phagocytosis as the potential treatment strategy and the basis for finding reliable damage biomarker for radiation-induced brain injury.

头颈部肿瘤是常见的恶性肿瘤之一，放疗是其最主要的治疗手段，但高达15%患者出现放射性脑损伤。我们前期工作提示放射后小胶质细胞(MG)髓鞘碎片清除障碍可能是放射后髓鞘修复受阻最终进展至坏死囊变的关键原因，但机制未明。TREM2是MG膜表面主要髓鞘吞噬受体，以跨膜结合型和可溶分泌型两种形式存在。跨膜结合型主要起清道夫受体的作用，可溶分泌型sTREM2可介导MG炎症反应。ADAM蛋白家族可以引起位于MG表面膜型TREM2的脱落，是介导TREM2由跨膜结合型转化为分泌型的主要蛋白酶，但如何进一步精准靶向调控ADAM蛋白亚型以促进MG髓鞘吞噬仍待进一步研究。本课题拟探索放射后MG髓鞘吞噬受体TREM2及其介导吞噬功能改变，通过靶向调控ADAMs-TREM2通路优化MG吞噬能力改善放射性脑损伤，并检测放脑患者生物样本sTREM2水平变化，为阐明放射性脑损伤发病机制及寻找可靠损伤生物标志物提供研究基础。

放射后小胶质细胞(MG)髓鞘碎片清除障碍可能是放射后髓鞘修复受阻最终进展至坏死囊变的关键原因，但机制未明。我们研究了放射后MG吞噬受体TREM2及其吞噬模式的改变，证实放射后发生小胶质细胞髓鞘吞噬障碍，髓鞘碎片和抑制因子Nogo-A蓄积，并阐明MG吞噬受体TREM2及其可溶分泌型片段sTREM2在照射后呈相关地动态改变；在体及离体实验并未证实在放射性脑损伤模型中ADAMs-TREM2通路的级联调控作用，探索了不同剂量组sTREM2对胶质细胞及神经元的作用，提示中等剂量可溶分泌型片段sTREM2组（s-100组）可能具有最佳的胶质细胞保护作用。同时，我们针对小胶质细胞在放射性脑损伤模型中的其他功能变化研究发现，小胶质细胞出现M1极化，且活性增强，与放射性脑损伤模型认知功能障碍相关。