Department of Neurology, the Third Xiangya Hospital of Central South University, No. 138 Tongzipo Road, Yuelu District, Changsha, Hunan, 410013, People's Republic of China.
Mol Neurobiol. 2022 Aug;59(8):5207-5221. doi: 10.1007/s12035-022-02902-7. Epub 2022 Jun 9.
The goal of this study was to characterize the mechanisms of long noncoding RNA (lncRNA) ZNF883 regulating NOD-like receptor 3 (NLRP3) inflammasome activation in epilepsy (EP). Rat and cellular EP models were established using pilocarpine and magnesium-free extracellular fluid, respectively, to detect the differential expression of ZNF883, microRNA (miR)-138-5p, ubiquitin-specific peptidase 47 (USP47), and NLRP3. The pathology of the hippocampal neurons was examined by whole-cell patch clamping. The expression of ZNF883, miR-138-5p, and USP47 was modified in epileptic neurons, and the EP rats were injected with sh-ZNF883. Then, alterations in ZNF883, miR-138-5p, and USP47 levels were measured. The histopathology of the hippocampus was detected, along with the detection of IL-6, IL-1β, TNF-α, and NLRP3. Neuronal apoptosis in the rat and cellular EP models was determined. The relationship among ZNF883, miR-138-5p, and USP47 as well as the regulation of NLRP3 ubiquitination by USP47 was determined. ZNF883, USP47, and NLRP3 were increasingly expressed and miR-138-5p was downregulated in epileptic neurons and rats, concurrent with aggravated inflammation and apoptosis. ZNF883 overexpression in epileptic neurons elevated USP47 expression. ZNF883 targeted miR-138-5p and miR-138-5p negatively regulated USP47. In epileptic neurons, inhibiting miR-138-5p or overexpressing USP47 partially reversed the ZNF883 silencing-induced inhibition on NLRP3 inflammasome activation, neuronal apoptosis, and epileptiform activity. ZNF883 silencing in EP rats decreased USP47 and NLRP3, increased miR-138-5p, and inhibited inflammation and apoptosis. USP47 reversed the ubiquitination of NLRP3. ZNF883 inhibits NLRP3 ubiquitination and promotes EP through upregulating USP47 by sponging miR-138-5p.
本研究旨在探讨长链非编码 RNA（lncRNA）ZNF883 调节 NOD 样受体 3（NLRP3）炎症小体激活在癫痫（EP）中的作用机制。使用匹罗卡品和无镁细胞外液分别建立大鼠和细胞 EP 模型，以检测 ZNF883、microRNA（miR）-138-5p、泛素特异性肽酶 47（USP47）和 NLRP3 的差异表达。通过全细胞膜片钳技术检测海马神经元的病理学变化。在癫痫神经元中修饰 ZNF883、miR-138-5p 和 USP47 的表达，并用 sh-ZNF883 注射 EP 大鼠。然后，测量 ZNF883、miR-138-5p 和 USP47 水平的变化。检测海马组织病理学变化，同时检测 IL-6、IL-1β、TNF-α 和 NLRP3。测定大鼠和细胞 EP 模型中神经元凋亡情况。确定 ZNF883、miR-138-5p 和 USP47 之间的关系以及 USP47 对 NLRP3 泛素化的调节作用。在癫痫神经元和大鼠中，ZNF883、USP47 和 NLRP3 的表达逐渐增加，miR-138-5p 下调，同时炎症和凋亡加重。癫痫神经元中 ZNF883 的过表达增加了 USP47 的表达。ZNF883 靶向 miR-138-5p，miR-138-5p 负调控 USP47。在癫痫神经元中，抑制 miR-138-5p 或过表达 USP47 部分逆转了 ZNF883 沉默引起的 NLRP3 炎症小体激活、神经元凋亡和癫痫样活动的抑制。EP 大鼠中 ZNF883 的沉默降低了 USP47 和 NLRP3，增加了 miR-138-5p，抑制了炎症和凋亡。USP47 逆转了 NLRP3 的泛素化。ZNF883 通过海绵 miR-138-5p 上调 USP47 抑制 NLRP3 泛素化并促进 EP。
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