Role of MS4A7 in Regulating Microglial Polarization and Neuroinflammation in Spinal Cord Injury via the cGAS-STING-NLRP3 Axis

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-06-16 DOI:10.1111/cns.70390

Xiangrui Li, Junpeng Liu, Youliang Deng, Fang Xing, Xihua Lu, Zhen Zhang, Changsheng Li

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引用次数: 0

Abstract

Background and Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

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MS4A7通过cGAS-STING-NLRP3轴调控脊髓损伤小胶质细胞极化和神经炎症的作用

背景和目的脊髓损伤（SCI）导致衰弱性神经功能障碍，主要是由于继发性损伤机制引发的炎症反应。小胶质细胞的激活和极化显著影响这种反应，促炎（M1）极化加剧损伤，抗炎（M2）极化促进修复。MS4A7是一种参与免疫调节的膜结合蛋白，与炎症有关，但其在脊髓损伤中的作用尚不清楚。本研究以cGAS-STING-NLRP3轴为重点，探讨MS4A7在脊髓损伤中调节小胶质细胞极化的功能及其对炎症反应的下游影响。方法采用小鼠脊髓损伤模型和BV2小胶质细胞相结合的方法。差异基因表达分析使用GSE93561数据集。利用shRNA和过表达质粒调节MS4A7的表达。通过免疫荧光、RT-qPCR和ELISA检测M1 （iNOS、IL-1β、TNF-α）和M2 （Arg1、IL-10、CD206）标记物的小胶质细胞极化。采用PI染色、LDH释放和NLRP3/GSDMD检测焦亡和炎性体活化。使用激活剂（diABZI）和抑制剂（C-176）评估cGAS-STING通路的作用，MCC950在药理学上抑制了NLRP3炎性体的活性。结果MS4A7在脊髓损伤组织中表达上调（p < 0.01）。敲低MS4A7可降低M1标记物（iNOS、IL-1β、TNF-α），升高M2标记物（Arg1、IL-10、CD206），促进抗炎极化（p < 0.05）。相反，MS4A7过表达通过NLRP3炎性体增强M1极化和焦亡。在体内，MS4A7敲低可改善运动恢复（BMS评分，p < 0.05），缓解疼痛相关行为（PWL和PWT， p < 0.01）。cGAS-STING通路介导NLRP3激活，药理抑制可减轻促炎作用，促进组织修复。在本研究中，我们发现MS4A7在脊髓损伤中通过cGAS-STING-NLRP3轴加重炎症并促进M1极化。靶向MS4A7及其相关通路为减轻神经炎症和促进恢复提供了潜在的治疗策略。这些发现为脊髓损伤病理生理的分子机制提供了新的见解，并强调MS4A7是一个有前景的治疗靶点。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.