Li Wenyao, Li Ying, Chen Yun, Wang Yan, Qian Lihua
Department of Special Inspection, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.
Department of Critical Care Medicine, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.
Sci Rep. 2025 Feb 12;15(1):5181. doi: 10.1038/s41598-025-88298-5.
Neurodegenerative diseases, characterized by impairments in cognition, memory, and movement, are becoming increasingly prevalent due to population aging, posing a significant threat to public health. Extensive evidence suggests that neuroinflammation, mediated by microglia, plays a crucial role in the development of these diseases. Notably, the vitamin D receptor (VDR) has been shown to regulate microglia activation by controlling the function of neuroprotective vitamin D. This study aims to elucidate the potential of VDR in modulating neuroinflammation. To mimic neuroinflammation, BV2 cells were treated with lipopolysaccharide (LPS) for 12 h. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the release of cytokines, including IL-1β, IL-2, IL-6, IL-10, IL-12, MCP-1, and TNF-α. Western blot assays were performed to assess relative protein expressions and succinylation modifications. Co-immunoprecipitation (Co-IP) experiments were conducted to determine the interaction between VDR and carnitine palmitoyltransferase 1A (CPT1A). Immunofluorescence staining was used to analyze the localization of VDR, CPT1A, COX-2, and CD11b. Our findings demonstrated that VDR expression was upregulated in BV2 cells exposed to LPS. Ectopic expression of VDR attenuated the inflammatory response and microglia activation. We discovered that carnitine palmitoyltransferase 1A (CPT1A) promoted VDR succinylation. Further investigations revealed that CPT1A enhanced VDR stability by binding to VDR, with lysine K117 being the primary succinylation site. Importantly, depletion of CPT1A abrogated the protective effects of VDR overexpression on microglia-mediated neuroinflammation. Our study highlighted that CPT1A functioned as a suppressor in neuroinflammation by facilitating VDR succinylation, offering potential therapeutic targets for the management of neurodegenerative diseases.
神经退行性疾病以认知、记忆和运动功能障碍为特征，随着人口老龄化，其发病率日益上升，对公众健康构成重大威胁。大量证据表明，由小胶质细胞介导的神经炎症在这些疾病的发展中起关键作用。值得注意的是，维生素D受体（VDR）已被证明可通过控制具有神经保护作用的维生素D的功能来调节小胶质细胞的激活。本研究旨在阐明VDR在调节神经炎症方面的潜力。为模拟神经炎症，用脂多糖（LPS）处理BV2细胞12小时。采用酶联免疫吸附测定（ELISA）法检测细胞因子IL-1β、IL-2、IL-6、IL-10、IL-12、MCP-1和TNF-α的释放。进行蛋白质免疫印迹分析以评估相关蛋白质的表达和琥珀酰化修饰。进行免疫共沉淀（Co-IP）实验以确定VDR与肉碱棕榈酰转移酶1A（CPT1A）之间的相互作用。采用免疫荧光染色法分析VDR、CPT1A、COX-2和CD11b的定位。我们的研究结果表明，暴露于LPS的BV2细胞中VDR表达上调。VDR的异位表达减弱了炎症反应和小胶质细胞的激活。我们发现肉碱棕榈酰转移酶1A（CPT1A）促进VDR的琥珀酰化。进一步研究表明，CPT1A通过与VDR结合增强了VDR的稳定性，赖氨酸K117是主要的琥珀酰化位点。重要的是，CPT1A的缺失消除了VDR过表达对小胶质细胞介导的神经炎症的保护作用。我们的研究强调，CPT1A通过促进VDR的琥珀酰化在神经炎症中起抑制作用，为神经退行性疾病的治疗提供了潜在的靶点。
