Balancing Anti-Inflammation and Neurorepair: The Role of Mineralocorticoid Receptor in Regulating Microglial Phenotype Switching After Traumatic Brain Injury

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-04-25 DOI:10.1111/cns.70404

Bin Zhang, Miao Bai, Mengshi Yang, Yumei Wang, Xueling Zhang, Xiyu Chen, Min Gao, Baiyun Liu, Guangzhi Shi

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Abstract

Background

As potent anti-inflammatory agents, glucocorticoids (GCs) have been widely used in the treatment of traumatic brain injury (TBI). However, their use remains controversial. Our previous study indicated that although dexamethasone (DEX) exerted anti-inflammatory effects and protected the blood–brain barrier (BBB) by activating the glucocorticoid receptor (GR) after TBI, it also impeded tissue repair processes due to excessive anti-inflammation. Conversely, fludrocortisone, acting as a specific mineralocorticoid receptor (MR) agonist, has shown potential in controlling neuroinflammation and promoting neurorepair, but the underlying mechanisms need further exploration.

Objective

This study aimed to explore the impact of the MR agonist fludrocortisone on microglia polarization, angiogenesis, functional rehabilitation, and associated mechanisms after TBI.

Methods

We established a mice controlled cortical impact model, and then immunofluorescence staining, western blot, rt-PCR, and MRI were performed to investigate microglia polarization, angiogenesis, and brain edema in the ipsilateral hemisphere after TBI and fludrocortisone treatment. Subsequently, functional tests including morris water maze, sucrose preference test, and forced swimming test were conducted to evaluate the effects of fludrocortisone treatment on neurofunction after TBI.

Results

Our results revealed that fludrocortisone suppressed neuroinflammation, enhanced angiogenesis and neuronal survival, and promoted functional rehabilitation by inducing a shift in microglia phenotype from M1 to M2 via the JAK/STAT6/PPARγ pathway. Additionally, the PI3K/Akt/HIF-1α pathway was involved in VEGF expression and in the process of angiogenesis.

Conclusion

Fludrocortisone, the specific MR agonist, exerted anti-neuroinflammatory and neuroprotective effects by regulating phenotypic switching of microglia from M1 to M2 rather than suppressing all types of microglia. Our study provided a theoretical basis for the therapeutic strategy of GCs targeting neuroinflammation after TBI.

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平衡抗炎和神经修复：矿化皮质激素受体在外伤性脑损伤后调节小胶质细胞表型转换中的作用

背景糖皮质激素作为一种有效的抗炎药物，已广泛应用于创伤性脑损伤的治疗。然而，它们的使用仍然存在争议。我们之前的研究表明，虽然地塞米松（DEX）在TBI后发挥抗炎作用，通过激活糖皮质激素受体（GR）保护血脑屏障（BBB），但它也因过度抗炎而阻碍组织修复过程。相反，氟化可的松作为一种特异性的矿物皮质激素受体（MR）激动剂，在控制神经炎症和促进神经修复方面显示出潜力，但其潜在机制有待进一步探索。目的探讨磁共振激动剂氟化可的松对脑外伤后小胶质细胞极化、血管生成、功能康复的影响及其相关机制。方法建立小鼠对照皮质冲击模型，采用免疫荧光染色、western blot、rt-PCR、MRI等方法观察脑外伤和氟可的松治疗后同侧半球小胶质细胞极化、血管生成及脑水肿情况。随后通过morris水迷宫、蔗糖偏好试验、强迫游泳试验等功能试验评价氟化可的松治疗对脑损伤后神经功能的影响。结果氟化可的松通过JAK/STAT6/PPARγ通路诱导小胶质细胞表型从M1向M2转变，从而抑制神经炎症，促进血管生成和神经元存活，促进功能康复。此外，PI3K/Akt/HIF-1α通路参与VEGF的表达和血管生成过程。结论特异性MR激动剂氟化可的松不是抑制所有类型的小胶质细胞，而是通过调节小胶质细胞M1向M2的表型转换来发挥抗神经炎和神经保护作用。我们的研究为GCs靶向TBI后神经炎症的治疗策略提供了理论依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.