Liu Zhiruo, Qin Qin, Wang Shisi, Kang Xinmei, Liu Yuxin, Wei Lei, Lu Zhengqi, Cai Wei, Hu Mengyan
Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China.
CNS Neurosci Ther. 2024 Dec;30(12):e70106. doi: 10.1111/cns.70106.
Monocyte-derived macrophages and microglia initially adopt an anti-inflammatory phenotype following stroke but later transition to a pro-inflammatory state. The mechanisms underlying this phenotypic shift remain unclear. This study investigates the activation dynamics of molecular signaling pathways in macrophages and microglia after stroke.
We utilized publicly available single-cell RNA sequencing datasets to examine the activation dynamics of molecular signaling pathways alongside the pro-inflammatory phenotype of macrophages and microglia. Male C57BL/6 mice underwent transient middle cerebral artery occlusion (tMCAO), with the STING inhibitor H151 administered to tMCAO mice. Neurobehavioral performance was assessed using rotarod, foot fault, novel object recognition, and water maze tests at 5-, 7-, 10-, and 14-days post-stroke. Primary microglia and bone marrow-derived macrophages were cultured for in vitro experiments.
Single-cell sequencing data indicated that the activation of STING and subsequent type I interferon signaling drove the phenotypic shift of microglia and macrophages toward a pro-inflammatory state in the stroke lesion. Immunostaining demonstrated that the emergence of pro-inflammatory microglia and macrophages aligned with the activation time course of STING and type I interferon signaling. Continuous phagocytosis by macrophages and microglia led to STING activation, which triggered type I interferon signaling and promoted the phenotypic shift. Inhibition of STING signaling prevented this transition, reduced neuroinflammation, and conferred protection against ischemic stroke.
These findings elucidated the critical role of STING-mediated type I interferon signaling in driving post-stroke neuroinflammation and underscored the potential of STING inhibition as a therapeutic strategy for alleviating neuroinflammatory responses following stroke.
单核细胞衍生的巨噬细胞和小胶质细胞在中风后最初呈现抗炎表型，但随后会转变为促炎状态。这种表型转变的潜在机制尚不清楚。本研究调查中风后巨噬细胞和小胶质细胞中分子信号通路的激活动态。
我们利用公开可用的单细胞RNA测序数据集来检查分子信号通路的激活动态以及巨噬细胞和小胶质细胞的促炎表型。雄性C57BL/6小鼠接受短暂性大脑中动脉闭塞（tMCAO），并将STING抑制剂H151给予tMCAO小鼠。在中风后5天、7天、10天和14天，使用转棒试验、足错试验、新物体识别试验和水迷宫试验评估神经行为表现。培养原代小胶质细胞和骨髓来源的巨噬细胞用于体外实验。
单细胞测序数据表明，STING的激活以及随后的I型干扰素信号传导促使中风病灶中的小胶质细胞和巨噬细胞向促炎状态转变。免疫染色显示，促炎小胶质细胞和巨噬细胞的出现与STING和I型干扰素信号传导的激活时间进程一致。巨噬细胞和小胶质细胞的持续吞噬作用导致STING激活，进而触发I型干扰素信号传导并促进表型转变。抑制STING信号传导可阻止这种转变，减轻神经炎症，并对缺血性中风起到保护作用。
这些发现阐明了STING介导的I型干扰素信号传导在中风后神经炎症中的关键作用，并强调了抑制STING作为减轻中风后神经炎症反应治疗策略的潜力。
