FKBP5 promotes pro-inflammatory microglial activation and neuronal injury through NF-κB/NLRP3 signaling in convulsive status epilepticus.

IF 3.1 4区医学 Q3 IMMUNOLOGY

Immunopharmacology and Immunotoxicology Pub Date : 2026-09-08 DOI:10.1080/08923973.2026.2725839

Haiping Zhang, Lin Wu, Ting Su, Mei Yuan

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引用次数: 0

Abstract

Background: Convulsive status epilepticus (CSE) triggers profound neuroinflammatory responses that exacerbate neuronal injury and impair long-term neurological recovery. FKBP5, a co-chaperone protein implicated in immune regulation, has been increasingly recognized as a modulator of inflammatory signaling. However, its role in microglial activation and neuroinflammation during CSE remains elusive.

Methods: A pilocarpine-induced mouse model of CSE was established to investigate FKBP5 expression dynamics in microglia. FKBP5 was silenced in vitro by siRNA transfection in primary microglia isolated from CSE model mice. Subsequently, microglia were co-cultured with primary cortical neurons to evaluate the impact of FKBP5-regulated microglial activation on neuronal survival and inflammatory response. Western blotting, immunofluorescence, and quantitative PCR were used to assess microglial activation phenotype markers, NF-κB activation, and NLRP3 inflammasome-related priming.

Results: FKBP5 expression was markedly upregulated in microglia following CSE, correlating with an enhanced pro-inflammatory phenotype and increased pro-inflammatory cytokine production. FKBP5 knockdown suppressed NF-κB activation, reduced NF-κB p65 nuclear translocation, and decreased NLRP3 inflammasome-related protein expression. In primary microglia, FKBP5 knockdown attenuated CSE-associated pro-inflammatory activation and decreased secretion of IL-1β and TNF-α. In microglia-neuron co-culture, FKBP5 knockdown reduced neuronal apoptosis and inflammatory injury, suggesting an indirect role of FKBP5 in modulating neuroinflammation and neuronal damage in the CSE context.

Conclusion: Our study identifies FKBP5 as an upstream modulator of NF-κB/NLRP3 signaling in microglia during convulsive status epilepticus. Targeting FKBP5 may represent a promising strategy to ameliorate neuroinflammation and neuronal injury in epilepsy.

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在惊厥癫痫持续状态中，FKBP5通过NF-κB/NLRP3信号通路促进促炎小胶质细胞激活和神经元损伤。

背景：惊厥性癫痫持续状态（CSE）引发深度神经炎症反应，加重神经元损伤，损害长期神经恢复。FKBP5是一种参与免疫调节的共伴侣蛋白，已越来越多地被认为是炎症信号的调节剂。然而，它在CSE期间的小胶质细胞激活和神经炎症中的作用仍然难以捉摸。方法：建立匹罗卡品诱导的CSE小鼠模型，观察FKBP5在小胶质细胞中的表达动态。通过siRNA转染CSE模型小鼠原代小胶质细胞，FKBP5基因被体外沉默。随后，将小胶质细胞与原代皮质神经元共培养，以评估fkbp5调节的小胶质细胞活化对神经元存活和炎症反应的影响。采用Western blotting、免疫荧光和定量PCR评估小胶质细胞活化表型标记、NF-κB活化和NLRP3炎症小体相关启动。结果：CSE后小胶质细胞中FKBP5表达显著上调，与促炎表型增强和促炎细胞因子产生增加相关。FKBP5下调抑制NF-κB活化，降低NF-κB p65核易位，降低NLRP3炎性小体相关蛋白表达。在初级小胶质细胞中，FKBP5敲低可减弱cse相关的促炎激活和IL-1β和TNF-α的分泌。在小胶质细胞-神经元共培养中，FKBP5敲低可减少神经元凋亡和炎症损伤，提示FKBP5在CSE背景下间接调节神经炎症和神经元损伤。结论：本研究确定FKBP5是惊厥癫痫持续状态中小胶质细胞NF-κB/NLRP3信号的上游调节剂。靶向FKBP5可能是改善癫痫患者神经炎症和神经元损伤的一种有希望的策略。

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来源期刊

Immunopharmacology and Immunotoxicology 医学-毒理学

CiteScore

5.40

自引率

0.00%

发文量

133

审稿时长

4-8 weeks

期刊介绍： The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).