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激活促进实验性脑出血小鼠的神经炎症和病理改变。相关论文于2025年4月8日发表在《中国药理学报》杂志上。

本研究探讨了cGAS-STING通路在脑出血中的作用。建立小鼠脑出血胶原酶模型。脑出血后D1或D3采集脑组织。该研究团队观察到脑出血小鼠血肿周围区域双链（dsDNA）水平和cGAS-STING通路的激活显著增加。血脑屏障渗透性STING拮抗剂H151 (10毫克/公斤,i.p)。显著降低ICH小鼠细胞凋亡，减轻血肿生长，改善运动障碍，同时抑制小胶质细胞STING通路，减少cGAS-STING通路下游炎症因子的产生/释放，减少NLRP3炎性小体激活和气皮蛋白D （GSDMD）诱导的小胶质细胞焦亡。小胶质细胞Sting条件敲除显著减轻ich诱导的神经炎症反应、病理损伤和运动功能障碍。这些结果表明，小胶质细胞STING通路通过激活NLRP3炎性体和小胶质细胞焦亡，促进脑出血小鼠脑病理损伤和行为缺陷。STING通路可能作为ich诱导的继发性脑损伤的潜在治疗靶点。

据了解，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，开发干预措施以减轻继发性神经免疫恶化是至关重要的。目前，没有有效的免疫调节药物可用于脑出血。环GMP-AMP合成酶（cGAS）干扰素刺激因子（STING）通路是最近发现的一种主要表达于中枢神经系统（CNS）内的小胶质细胞的先天免疫感应通路，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.

DOI: 10.1038/s41401-025-01540-8

Source: https://www.nature.com/articles/s41401-025-01540-8