Glut1作为糖代谢能量开关驱动NETosis参与ANCA相关性血管炎作用机制研究

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease with serious kindey injured. Neutrophil extracellular traps (NETs）, which formation and release called NETosis, as the main sources of antigens exposured in AAV. We found that NETs was significantly promoted in AAV patients, and was closely related to kindey injured. NETosis is major regulated by Nox-generated ROS and ROS-dependent autophagy. However, NETosis could not be completely inhibited by blocking autophagy,which means other pathways involved in ROS-dependent NETosis. Glycometabolism is indispensable for NETs, and Glucose transport 1 (Glut1) is the key of glycometabolism in neutrophils. Based on the above, we hypothesized that NETosis could be regulated by Glut1 relevanted glycometabolism via AMPK pathway under Nox-generated ROS. We will analyse the glycometabolism and NETosis from AAV patients, then observe the effect of NOX-regulated Glut1. At last, our hypothesis will be verified in the NETs-mDC AAV mouse. The aim is to seek regulation targets of NETosis for preferable therapies in AAV.

抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）是多系统受累的自身免疫性疾病。中性粒细胞胞外捕网（NETs）的形成及释放（NETosis）是AAV自身抗原暴露的关键环节。既往报道及课题组前期发现AAV患者NETosis释放增多与肾脏损伤相关。NETosis主要受NOX来源的活性氧(ROS)调节。我们发现阻断ROS依赖的自噬并不能完全阻断NETosis，提示存在ROS依赖的其它途径。糖代谢是NETosis释放所必需环节，Glut1是葡萄糖关键调控开关。故我们推测：NOX来源的ROS可能通过Glut1影响糖代谢而调控NETosis形成，AMPK通路可能参与其中。为此，本项目拟从临床观察AAV患者中性粒细胞糖代谢及NETosis情况，体外实验明确NOX调控Glut1对NETosis影响，最后在mDC摄取并递呈NETs的AAV小鼠模型验证，寻求调控NETosis对AAV肾脏损伤干预点。

抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）是多系统受累的自身免疫性疾病。中性粒细胞胞外捕网（NETs）的形成及释放是AAV自身抗原暴露的关键环节。既往报道及课题组前期发现AAV患者NETs释放增多与肺部损伤及肺纤维化形成、肾脏损伤相关。NETs主要受NOX来源的活性氧(ROS)调节。我们发现糖代谢是NETs释放所必需环节，Glut1是葡萄糖关键调控开关。本项目先分析AAV患者中性粒细胞Glut-1表达及NETs形成。继而构建动物模型，我们发现NOX来源的ROS受Glut-1影响糖代谢调控，且阻断Glut-1减少NETs，减轻肺部损伤。同时，我们发现临床药物盐酸青藤碱能够显著改善肺纤维化形成，体外实验证实其机制通过抑制中性粒细胞Glut-1表达，减少其葡萄糖摄取和ROS，从而减少NETs。本项目从临床观察AAV患者中性粒细胞糖代谢及NETs情况，动物实验证实调控Glut-1能够减轻AAV模型肺损伤，最后体外实验明确调控Glut1对NETs影响。本项目探究并发现Glut-1作用及其调控药物盐酸青藤碱减少NETs形成，为减轻AAV疾病中肺纤维化进一步阐明其调控机制和寻求治疗靶点。