FGF21, a modulator of astrocyte reactivity, protects against ischemic brain injury through anti-inflammatory and neurotrophic pathways.

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-02-28 DOI:10.1038/s41401-024-01462-x
Dong-Xue Wang, Wen-Ting Huang, Jun-Feng Shi, Fei Liu, Wen-Yi Jiang, Ke-Yang Chen, Shu-Yang Zhang, Xiao-Kun Li, Li Lin
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引用次数: 0

Abstract

Ischemic stroke is a frequent cause of mortality and disability, and astrocyte reactivity is closely associated with injury outcomes. Fibroblast growth factor 21 (FGF21), an endogenous regulator, has been shown to perform pleiotropic functions in central nervous system (CNS) disorders. However, studies on neurological diseases have paid little attention to the effects and detailed mechanisms of FGF21 in astrocytes. Here, we found elevated serum levels of FGF21 in stroke patients and transient middle cerebral artery occlusion (tMCAO) mice. In the peri-infarct cortex, microglia and astrocytes serve as sources of FGF21 in addition to neurons. MRI and neurobehavioral assessments of wild-type (WT) and FGF21-/- tMCAO model mice revealed a deteriorated consequence of the loss of FGF21, with exacerbated brain infarction and neurological deficits. Additionally, combined with the pharmacological treatment of WT mice with recombinant human FGF21 (rhFGF21) after tMCAO, FGF21 was identified to suppress astrocytic activation and astrocyte-mediated inflammatory responses after brain ischemia and participated in controlling the infiltration of peripheral inflammatory cells (including macrophages, neutrophils, monocytes, and T cells) by modulating chemokines expression (such as Ccl3, Cxcl1, and Cxcl2) in astrocytes. Furthermore, rhFGF21 was shown to boost the production of neurotrophic factors (BDNF and NGF) in astrocytes, and by which rescued neuronal survival and promoted synaptic protein expression (postsynaptic density protein-95 (PSD-95), synaptotagmin 1 (SYT1), and synaptophysin) in neurons after ischemic injury. Overall, our findings implicate that FGF21 acts as a suppressor of astrocyte activation, and exerts anti-inflammatory and neurotrophic effects after ischemic brain injury through its action on astrocytes, offering an alternative therapeutic target.

FGF21是一种星形胶质细胞反应性调节剂,可通过抗炎和神经营养途径预防缺血性脑损伤。
缺血性中风是导致死亡和残疾的常见原因,而星形胶质细胞的反应性与损伤结果密切相关。成纤维细胞生长因子 21(FGF21)是一种内源性调节因子,已被证明在中枢神经系统(CNS)疾病中具有多种功能。然而,有关神经系统疾病的研究很少关注 FGF21 在星形胶质细胞中的作用和详细机制。在这里,我们发现中风患者和短暂性大脑中动脉闭塞(tMCAO)小鼠血清中的 FGF21 水平升高。在梗死周围皮层中,除神经元外,小胶质细胞和星形胶质细胞也是 FGF21 的来源。对野生型(WT)和FGF21-/- tMCAO模型小鼠进行的核磁共振成像和神经行为评估显示,FGF21缺失会导致脑梗塞加重和神经功能缺损。此外,结合重组人 FGF21(rhFGF21)药理学治疗 tMCAO 后的 WT 小鼠,发现 FGF21 可抑制脑缺血后星形胶质细胞的活化和星形胶质细胞介导的炎症反应,并通过调节星形胶质细胞中趋化因子(如 Ccl3、Cxcl1 和 Cxcl2)的表达,参与控制外周炎症细胞(包括巨噬细胞、中性粒细胞、单核细胞和 T 细胞)的浸润。此外,rhFGF21 还能促进星形胶质细胞中神经营养因子(BDNF 和 NGF)的产生,从而挽救神经元的存活,并促进缺血损伤后神经元中突触蛋白(突触后密度蛋白-95(PSD-95)、突触标记蛋白 1(SYT1)和突触素)的表达。总之,我们的研究结果表明,FGF21 可抑制星形胶质细胞的活化,并通过其对星形胶质细胞的作用在缺血性脑损伤后发挥抗炎和神经营养作用,从而提供了另一种治疗靶点。
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
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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