SOCS3抑制与间歇性缺氧小鼠模型中的海马炎症相关

文献信息

中文摘要

背景/目的： 间歇性缺氧（IH）是阻塞性睡眠呼吸暂停（OSA）的特征，与海马炎症和认知功能障碍相关。我们在小鼠IH模型和BV2细胞中检测了SOCS3表达以及可能的MALAT1/EZH2/H3K27me3调控关系。方法：将C57BL/6J小鼠暴露于IH 4周，随后进行Morris水迷宫测试并分析海马组织。将BV2细胞暴露于IH，并用于转染、RNA免疫沉淀和染色质免疫沉淀实验。结果：在小鼠中，IH与较差的水迷宫表现、较低的海马SOCS3以及较高水平的炎症标志物、MALAT1和H3K27me3相关。在BV2细胞中观察到相似的分子变化。SOCS3过表达降低了BV2细胞中TRAF6、总NF-κB p65、TNF-α和IL-1β蛋白水平。MALAT1可被EZH2免疫沉淀富集，H3K27me3在SOCS3启动子处富集，而MALAT1敲低降低了总H3K27me3，同时增加了SOCS3蛋白。结论：这些发现将SOCS3降低与IH后的海马炎症相关联，并支持进一步研究MALAT1和EZH2在其调控中的作用。体内炎症标志物的细胞来源以及EZH2的因果作用需要直接检验。

英文摘要

Background/Objectives: Intermittent hypoxia (IH), a feature of obstructive sleep apnea (OSA), is associated with hippocampal inflammation and cognitive dysfunction. We examined SOCS3 expression and a possible MALAT1/EZH2/H3K27me3 regulatory relationship in a mouse IH model and BV2 cells. Methods: C57BL/6J mice were exposed to IH for 4 weeks, followed by Morris water maze testing and analysis of hippocampal tissue. BV2 cells were exposed to IH and used for transfection, RNA immunoprecipitation, and chromatin immunoprecipitation experiments. Results: In mice, IH was associated with poorer water maze performance, lower hippocampal SOCS3, and higher levels of inflammatory markers, MALAT1, and H3K27me3. Similar molecular changes were observed in BV2 cells. SOCS3 overexpression reduced TRAF6, total NF-κB p65, TNF-α, and IL-1β protein levels in BV2 cells. MALAT1 was enriched by EZH2 immunoprecipitation, H3K27me3 was enriched at the SOCS3 promoter, and MALAT1 knockdown reduced total H3K27me3 while increasing SOCS3 protein. Conclusions: These findings associate reduced SOCS3 with hippocampal inflammation after IH and support further investigation of MALAT1 and EZH2 in its regulation. The cellular source of the in vivo inflammatory markers and the causal role of EZH2 require direct testing.