中性粒细胞胞膜与胞核mGluR5协同促进颅脑创伤后抑郁的机制研究

The inflammatory response is highly involved in trauma-induced depression after traumatic brain injury (TBI). While it is still ill-defined about how the uncontrolled inflammation drives to depression and other neurodegenerative diseases. Based on preliminary study, we found that metabotropic glutamate receptor 5 (mGluR5) from peripheral neutrophil significantly promotes post-traumatic depression from two spects: by interacting with CXCR1 in cytomembrane to promote neutrophil migration from blood vessel to brain; by up-regulating neutrophil gelatinase-associated lipocalin (NGAL) in karyotheca to jeopardize inherent brain cells. We hypothesize that "mGluR5-CXCR1" in cytomembrane and "mGluR5-NGAL" in nuclear might act synergistically, facilitating neutrophil migration and accelerating the development of depression after TBI. We would like to confirm our hypothesis in cell and animal models combined with clinical specimen analysis. Protein interaction analysis, gene expression regulation technology and signal pathway analysis will also be used to further decipher the molecular mechanisms. The aim of this project is to further understand the roles and mechanisms of neutrophils in depression post TBI, and to provide a possible therapeutic point for clinical intervention in the future.

颅脑创伤后炎症反应与损伤后高发的并发症颅脑创伤后抑郁密切相关，但具体机制不清。我们基于前期发现“外周血中性粒细胞的代谢型谷氨酸受体5（mGluR5）显著促进颅脑创伤后抑郁且mGluR5在胞膜与CXCR1存在互作，可促进中性粒细胞趋化；而在胞核mGluR5可上调中性粒细胞明胶酶相关脂质运载蛋白（NGAL）这一促抑郁分子的表达”，推测：mGluR5可能通过胞膜“mGluR5-CXCR1”途径促进中性粒细胞浸润入脑致炎和胞核“mGluR5-NGAL”途径介导中性粒细胞调控脑内细胞功能，两者协同促进了颅脑创伤后抑郁的发生发展进程。因此，拟通过蛋白质互作解析、基因表达调控技术、信号通路分析等在细胞及动物模型中进行阐明，并结合临床标本监测加以证实。旨在深入认知中性粒细胞这一重要的外周炎性细胞在颅脑创伤后抑郁发生发展中的作用及调控机理，进而为临床干预提供有效的切入点。

颅脑创伤在平时和战时均具有高发生率、高死亡率和高致残率的特点。对其的救治不仅仅在于损伤后急性期对生命和脑功能的保护，更困难的是在于对损伤后漫长的各类并发症的处理。抑郁是颅脑创伤最常见的并发症之一，与创伤后炎症反应密切相关，但具体机制不清。我们探究了中性粒细胞代谢型谷氨酸受体5（mGluR5）在胞膜与CXCR1存在互作，可促进中性粒细胞趋化；而在胞核mGluR5可上调中性粒细胞明胶酶相关脂质运载蛋白（NGAL）这一促抑郁分子表达，从而共同促进了抑郁的发生。此外，我们还发现，TBI后叉头框蛋白O家族亚型1（FOXO1）的高表达能够靶向调控多功能蛋白聚糖（VCAN），引起中性粒细胞凋亡延迟，炎性介质释放能力增加，并进一步加重急性期脑损伤。本基金的相关研究聚焦颅脑创伤后，微环境的改变导致外周中性粒细胞的功能发生重塑的分子机制，加深了对炎症和TBI后预后的认识，旨在为临床相关疾病的诊治提供有效的切入点。