IL-33介导Treg细胞调控硬脑膜淋巴管的生成和功能进而促进TBI后功能恢复的作用及机制研究

脑外伤（TBI）后物质代谢紊乱是治疗的重要靶点，已知硬脑膜淋巴管(mLVs)是颅内物质代谢引流的关键通道，且抑制mLVs引流可加剧TBI神经损伤，但尚未知促进mLVs生成和引流是否改善TBI预后。申请人前期证实白细胞介素-33（IL-33）含量高的TBI患者预后良好，且IL-33可提高TBI小鼠脑组织中调节性T细胞（Treg）比例，同时已知Treg与淋巴管（LVs）的功能和数量密切相关，故假说: IL-33可介导Treg调控mLVs的生成和功能、促进TBI颅内有害物质排出和神经损伤修复。拟依托TBI模型，应用小动物PET-MRI、荧光示踪等方法探明①IL-33对TBI后炎性反应、mLVs的形态和功能及神经功能的影响，确定IL-33调控mLVs生成及其相关信号通路；②在体内外实验中确定Treg是否为IL-33调控mLVs生成与引流及其相关信号通路中关键细胞。为创新TBI诊疗策略提供理论依据。

Disturbance of material metabolism after traumatic brain injury (TBI) is an important target for treatment.Meningeal lymphatic vessels (mLVs) are known to be the key pathway for the metabolic drainage of intra-cranial material, and inhibiting the drainage of mLVs can aggravate TBI nerve damage. However, it is still unknown whether promoting the generation and drainage of mLVs can improves the prognosis of TBI.The applicant confirmed that TBI patients with high levels of interleukin-33 (IL-33) have a good prognosis, and IL-33 can increase the proportion of regulatory T cells (Treg) in the brain tissue of TBI mice. In addition,there are also reports showed that Treg is closely related to the function and quantity of lymphatic vessels (LVs), so we hypothesized that IL-33 can mediate Treg to regulate the generation and function of mLVs, which could promote the drainage of harmful substances and repair nerve damage in TBI. Based on the TBI model, small animal PET-MRI, fluorescence tracing and other methods are used to explore ①the effects of IL-33 on the inflammatory response,the morphology,the function and generation of mLVs and the neurological function after TBI as well as its correlation signal pathway; ②whether Treg is the key cell in the process of IL-33 in regulating the generation and drainage of mLVs and related signal pathways in vivo and in vitro. This project could provide a theoretical basis for innovation of TBI diagnosis and treatment strategies.