CPT1A ameliorates microglia-induced neuroinflammation via facilitating VDR succinylation.

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.