Li Xiangrui, Liu Junpeng, Deng Youliang, Xing Fang, Lu Xihua, Zhang Zhen, Li Changsheng
Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
Department of Anesthesiology, Xinqiao Hospital, the Third Military Medical University, Chongqing, China.
CNS Neurosci Ther. 2025 Jun;31(6):e70390. doi: 10.1111/cns.70390.
Spinal cord injury (SCI) leads to debilitating neurological deficits primarily due to the inflammatory response triggered by secondary injury mechanisms. Microglial activation and polarization significantly influence this response, with pro-inflammatory (M1) polarization exacerbating damage and anti-inflammatory (M2) polarization promoting repair. MS4A7, a membrane-bound protein involved in immune regulation, has been implicated in inflammation, but its role in SCI remains unexplored. This study investigates the function of MS4A7 in modulating microglial polarization and its downstream effects on the inflammatory response in SCI, focusing on the cGAS-STING-NLRP3 axis.
A combination of in vivo and in vitro approaches, including mouse SCI models and BV2 microglial cells, was employed. Differential gene expression analysis was conducted using the GSE93561 dataset. MS4A7 expression was modulated using shRNA and overexpression plasmids. Microglial polarization was assessed via immunofluorescence, RT-qPCR, and ELISA for M1 (iNOS, IL-1β, TNF-α) and M2 (Arg1, IL-10, CD206) markers. Pyroptosis and inflammasome activation were examined using PI staining, LDH release, and NLRP3/GSDMD assays. The role of the cGAS-STING pathway was evaluated using activators (diABZI) and inhibitors (C-176), and NLRP3 inflammasome activity was pharmacologically inhibited with MCC950.
MS4A7 was significantly upregulated in SCI tissues (p < 0.01). Knockdown of MS4A7 reduced M1 markers (iNOS, IL-1β, and TNF-α) and increased M2 markers (Arg1, IL-10, and CD206), promoting anti-inflammatory polarization (p < 0.05). Conversely, MS4A7 overexpression enhanced M1 polarization and pyroptosis through the NLRP3 inflammasome. In vivo, MS4A7 knockdown improved locomotor recovery (BMS score, p < 0.05) and alleviated pain-related behaviors (PWL and PWT, p < 0.01). The cGAS-STING pathway mediated NLRP3 activation, with pharmacological inhibition mitigating pro-inflammatory effects and favoring tissue repair.
In this study, we found that MS4A7 exacerbates inflammation and promotes M1 polarization via the cGAS-STING-NLRP3 axis in SCI. Targeting MS4A7 and its associated pathways offers potential therapeutic strategies to mitigate neuroinflammation and enhance recovery. These findings provide new insights into the molecular mechanisms underlying SCI pathophysiology and highlight MS4A7 as a promising therapeutic target.
脊髓损伤（SCI）主要由于继发性损伤机制引发的炎症反应导致使人衰弱的神经功能缺损。小胶质细胞的激活和极化对这种反应有显著影响，促炎（M1）极化会加剧损伤，而抗炎（M2）极化则促进修复。MS4A7是一种参与免疫调节的膜结合蛋白，与炎症有关，但其在SCI中的作用仍未得到探索。本研究调查了MS4A7在调节小胶质细胞极化及其对SCI炎症反应的下游影响中的作用，重点关注cGAS-STING-NLRP3轴。
采用体内和体外相结合的方法，包括小鼠SCI模型和BV2小胶质细胞。使用GSE93561数据集进行差异基因表达分析。使用shRNA和过表达质粒调节MS4A7的表达。通过免疫荧光、RT-qPCR以及针对M1（诱导型一氧化氮合酶、白细胞介素-1β、肿瘤坏死因子-α）和M2（精氨酸酶1、白细胞介素-10、CD206）标志物的ELISA评估小胶质细胞极化。使用PI染色、乳酸脱氢酶释放和NLRP3/GSDMD检测来检查细胞焦亡和炎性小体激活。使用激活剂（diABZI）和抑制剂（C-176）评估cGAS-STING途径的作用，并用MCC950药理学抑制NLRP3炎性小体活性。
MS4A7在SCI组织中显著上调（p < 0.01）。敲低MS4A7可降低M1标志物（诱导型一氧化氮合酶、白细胞介素-1β和肿瘤坏死因子-α）并增加M2标志物（精氨酸酶1、白细胞介素-10和CD206），促进抗炎极化（p < 0.05）。相反，MS4A7过表达通过NLRP3炎性小体增强M1极化和细胞焦亡。在体内，敲低MS4A7可改善运动功能恢复（BMS评分，p < 0.05）并减轻疼痛相关行为（PWL和PWT，p < 0.01）。cGAS-STING途径介导NLRP3激活，药理学抑制可减轻促炎作用并有利于组织修复。
在本研究中，我们发现MS4A7通过SCI中的cGAS-STING-NLRP3轴加剧炎症并促进M1极化。靶向MS4A7及其相关途径提供了减轻神经炎症和促进恢复的潜在治疗策略。这些发现为SCI病理生理学的分子机制提供了新的见解，并突出了MS4A7作为一个有前景的治疗靶点。
