LncRNA-PCat19 acts as a ceRNA of miR-378a-3p to facilitate microglia activation and accelerate chronic neuropathic pain in rats by promoting KDM3A-mediated BDNF demethylation

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology Pub Date : 2024-04-20 DOI:10.1016/j.molimm.2024.04.003

Ziyu Zhao, Xingxing Zheng, Hui Wang, Jiao Guo, Ruixia Liu, Guang Yang, Miao Huo

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Abstract

The pathogenesis of neuropathic pain (NP) is complex, and there are various pathological processes. Previous studies have suggested that lncRNA PCAT19 is abnormally expressed in NP conduction and affects the occurrence and development of pain. The aim of this study is to analyze the role and mechanism of PCAT19 in NP induced by chronic compressive nerve injury (CCI) in mice. In this study, C57BL/6 mice were applied to establish the CCI model. sh-PCAT19 was intrathecally injected once a day for 5 consecutive days from the second day after surgery. We discovered that PCat19 level was gradually up-regulated with the passage of modeling time. Downregulation of Iba-1-positive expression, M1/M2 ratio of microglia, and pro-inflammatory factors in the spinal cords of CCI-mice after PCat19 knock-downed was observed. Mechanically, the expression of miR-378a-3p was negatively correlated with KDM3A and PCat19. Deletion of KDM3A prevented H3K9me2 demethylation of BDNF promoter and suppressed BDNF expression. Further, KDM3A promotes CCI-induced neuroinflammation and microglia activation by mediating Brain-derived neurotrophic factor (BDNF) demethylation. Together, the results suggest that PCat19 may be involved in the development of NP and that PCat19 shRNA injection can attenuate microglia-induced neuroinflammation by blocking KDM3A-mediated demethylation of BDNF and BDNF release.

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LncRNA-PCat19作为miR-378a-3p的ceRNA，通过促进KDM3A介导的BDNF去甲基化，促进小胶质细胞活化并加速大鼠的慢性神经病理性疼痛

神经病理性疼痛（NP）的发病机制复杂，病理过程多样。以往的研究表明，lncRNA PCAT19在NP传导过程中异常表达，并影响疼痛的发生和发展。本研究旨在分析 PCAT19 在小鼠慢性压迫性神经损伤（CCI）诱导的 NP 中的作用和机制。本研究应用C57BL/6小鼠建立CCI模型，从术后第二天起连续5天每天一次鞘内注射sh-PCAT19。我们发现，随着建模时间的推移，PCat19的水平逐渐上调。PCat19敲除后，CCI小鼠脊髓中Iba-1阳性表达、小胶质细胞M1/M2比例和促炎因子均出现下调。从机制上看，miR-378a-3p 的表达与 KDM3A 和 PCat19 呈负相关。KDM3A的缺失阻止了BDNF启动子的H3K9me2去甲基化，抑制了BDNF的表达。此外，KDM3A通过介导脑源性神经营养因子（BDNF）去甲基化，促进CCI诱导的神经炎症和小胶质细胞活化。这些结果表明，PCat19可能参与了NP的发展，PCat19 shRNA注射可以通过阻断KDM3A介导的BDNF去甲基化和BDNF释放来减轻小胶质细胞诱导的神经炎症。

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来源期刊

Molecular immunology 医学-免疫学

CiteScore

6.90

自引率

2.80%

发文量

324

审稿时长

50 days

期刊介绍： Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.