小胶质细胞STING激活促进实验性脑出血小鼠的神经炎症和病理改变

上海交通大学丁春勇小组的一项最新研究发现，小胶质细胞STING的激活促进了试验性脑溢血小鼠的神经炎症和病理变化。相关论文于2025年4月8日在《中国药理学报》杂志上发表。

本文对cGAS-STING通道在脑溢血中的作用进行了探讨。建立小鼠脑溢血胶原酶模型。D1或D3在脑出血后采集大脑。该研究小组观察到脑溢血小鼠血肿周边地区的双链(dsDNA)CGAS-STING通道的能力和激活显著增加。H151515血脑屏障透水性STING拮抗剂 (10mg/KG,i.p)。在抑制小胶质细胞STING通道的同时，显著减少ICH小鼠细胞坏死，缓解血肿生长，改善运动障碍，减少CGAS-STING通道下游炎症因子的产生/释放，减少NLRP3炎症体激活和气皮蛋白D (GSDMD)诱发的小胶质细胞焦亡。小胶质细胞Sting条件敲除神经炎症反应、病理损伤和运动功能障碍，显著缓解ich诱发。通过激活NLRP3炎性体和小胶质细胞焦亡，小胶质细胞STING通道可以促进脑溢血小鼠脑病理损伤和行为缺陷。在ich诱导下，STING通道可作为继发性脑损伤的潜在治疗目标。

众所周知，神经炎症是继发性脑损伤的重要诱因，在脑出血的病理过程和预后中起着至关重要的作用。因此，为了缓解继发性神经免疫的恶化，开发治疗措施非常重要。目前脑出血没有有效的免疫调节药物。环GMP-AMP合成酶(cGAS)干扰素刺激因子(STING)通道是近期发现的一种主要表达在中枢系统中。(CNS)小胶质细胞的先天性免疫感应通道，与多种神经系统疾病的病理生理有关。

附：英文原文

Title: Microglial STING activation promotes neuroinflammation and pathological changes in experimental mice with intracerebral haemorrhage

Author: Xue, Yu-xiao, Chen, Yi-jun, Qin, Mei-zhen, Shang, Fan-fan, Lu, Yi-ting, Sun, Yu-hao, Bian, Liu-guan, Zhang, Ao, Yu, Yang, Ding, Chun-yong

Issue&Volume: 2025-04-08

Abstract: Neuroinflammation, a significant contributor to secondary brain injury, plays a critical role in the pathological process and prognosis of intracerebral haemorrhage (ICH). Thus, developing interventions to mitigate secondary neuroimmune deterioration is of paramount importance. Currently, no effective immunomodulatory drugs are available for ICH. The cyclic GMP-AMP synthase (cGAS)stimulator of interferon genes (STING) pathway is a recently identified innate immune-sensing pathway primarily expressed in microglia within the central nervous system (CNS) that has been implicated in the pathophysiology of various neurological diseases. In this study we investigated the role of cGAS-STING pathway in ICH. A collagenase model of ICH was established in mice. Brain tissues were collected on D1 or D3 post-ICH. We observed a significant increase in double-stranded (dsDNA) levels and activation of the cGAS-STING pathway in the perihaematomal region of ICH mice. Administration of a blood brain barrier-permeable STING antagonist H151 (10mg/kg, i.p.) significantly decreased cell apoptosis, alleviated hematoma growth, and improved motor impairments in ICH mice, accompanied by inhibiting the STING pathway in microglia, reducing production/release of the cGAS-STING pathway downstream inflammatory factors, NLRP3 inflammasome activation and gasdermin D (GSDMD)-induced microglial pyroptosis. Microglial Sting conditional knockout significantly mitigated ICH-induced neuroinflammatory responses, pathological damage and motor dysfunction. These results suggest that the microglial STING pathway promotes brain pathological damage and behavioural defects in ICH mice by activating the NLRP3 inflammasome and microglial pyroptosis. The STING pathway may serve as a potential therapeutic target for ICH-induced secondary brain injury.