SENP1通过PPARγ调控间歇低氧小胶质细胞极化的作用及机制

Obstructive sleep apnea hypopnea syndrome (OSAS) can induce neurocognitive dysfunction, which is contributed to the inflammatory reaction of microglia caused by intermittent hypoxia (IH). However, the specific mechanism has not yet been elucidated. In our previous work, we found that expression of SENP1 was down-regulated by IH in BV2 cells, and over-expression of SENP1 could significantly inhibit the up-regulation of expression of proinflammatory factors induced by IH, thus inhibiting microglial inflammation and reducing the rate of cell apoptosis. Other studies have shown that SENP1 is a protease that specifically de-SUMOylates SUMOylated Sharp-1, while Sharp-1 is a transcriptional inhibitory factor regulating PPARγ activity. Based on the key role of PPARγ in regulating microglia polarization and our previous results, we speculate that SENP1 promotes M1 polarization as well as inhibits M2 polarization through increasing SUMOylation of Sharp-1 thus inhibiting PPARγ expression, finally aggravates neuroinflammation and causes neurotrosis. In this research, we intend to explore role of SENP1 on microglia M1/M2 polarization in IH condition and the mechanism, clarifying its role in neuroinflammation and verifying the results by animal model. This study could benefit further understanding of neurocogtive dysfunction caused by OSAS and provide theoretic basis and potential new target for prevention and treatment.

阻塞性睡眠呼吸暂停低通气综合征可导致神经认知功能障碍。这与其间歇低氧（IH）致小胶质细胞炎症有关，但未知是否影响小胶质细胞极化。我们前期研究示IH诱导小胶质细胞中SENP1表达水平下调，SENP1过表达可显著抑制由IH引起的炎症反应并降低细胞凋亡率，而SENP1是Sharp-1去SUMO化修饰的关键酶，可通过影响Sharp-1的SUMO化修饰，调控PPARγ表达水平。鉴于PPARγ在小胶质细胞极化中有重要作用，并基于我们前期结果，我们推测IH诱导小胶质细胞SENP1下调，引起Sharp-1的SUMO化修饰增加，PPARγ表达下降，导致M1型极化比例上升，M2型极化比例下降，神经炎症反应加剧，诱导神经损伤。本研究拟通过体外实验研究IH对小胶质细胞极化的影响，明确SENP1在小胶质细胞极化中的作用及机制，并通过体内动物模型加以验证。本研究为进一步防治该疾病的神经系统并发症提供理论基础和新靶点。

神经认知功能损害是阻塞性睡眠呼吸暂停综合征(OSAS)最常见的并发症之一，这与夜间间歇低氧（IH）密切相关，具体机制尚未阐明。本研究证实IH通过下调小胶质细胞内SUMO特异性蛋白酶1（SENP1）表达下降，调控PPARγ/NF-kB信号通路和小胶质细胞迁移的关键蛋白发生SUMO化，释放炎性因子诱导小胶质细胞极化及神经元凋亡，引起神经认知功能障碍。过氧化物酶体增殖物激活受体γ（PPARγ）和NF-kB必须调节蛋白(NEMO)的SUMO化在其中起着重要作用。本研究结果对于阐明SENP1在IH诱导小胶质细胞极化、神经元淀粉样蛋白沉积和神经元凋亡及OSAS患者认知功能障碍中的作用有重要指导价值。本基金资助下，已发表标注基金号的SCI论著3篇，中文核心期刊综述1篇，学术会议交流论文（讲座报告）2篇，另有2篇 SCI 论著正在投稿中。