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LncRNA ZNF883-Mediated NLRP3 Inflammasome Activation and Epilepsy Development Involve USP47 Upregulation

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Abstract

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.

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Data Availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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Funding

This study received grants from the Youth Science Foundation of the National Natural Science Foundation of China (No. 81901329) and the General Program of the National Natural Science Foundation of Hunan Province (No. 2021JJ30990).

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Lina Gong conceived the ideas. Chen Zhang designed the experiments. Lina Gong performed the experiments. Yaru Han analyzed the data. Ru Chen and Pu Yang provided critical materials. Lina Gong and Yaru Han wrote the manuscript. Chen Zhang supervised the study. All the authors have read and approved the final version for publication.

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Correspondence to Chen Zhang.

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Gong, L., Han, Y., Chen, R. et al. LncRNA ZNF883-Mediated NLRP3 Inflammasome Activation and Epilepsy Development Involve USP47 Upregulation. Mol Neurobiol 59, 5207–5221 (2022). https://doi.org/10.1007/s12035-022-02902-7

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