NLRP3 inflammasome signaling as an early molecular response is negatively controlled by miR-186 in CFA-induced prosopalgia mice

The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most frequently studied in the central nervous system and has been linked to neuropathic pain. In this study, a post-translational mechanism of microRNA (miR)-186 via regulating the expression of NLRP3 in the complete Freund's adjuvant (CFA)-treated mice was investigated. The injection of CFA was used to induce trigeminal neuropathic pain in mice. miRs microarray chip assay was performed in trigeminal ganglions (TGs). CFA treatment significantly increased the mRNA expression of NLRP3, interleukin (IL)-1β, and IL-18 in TGs compared to the control group. Moreover, 26 miRs were differentially expressed in TGs from trigeminal neuropathic pain mice, and the expression of miR-186 showed the lowest level of all the miRs. Further examination revealed that NLRP3 was a candidate target gene of miR-186. We delivered miR-186 mimics to CFA-treated mice. The head withdrawal thresholds of the CFA-treated mice were significantly increased by miR-186 mimics injection compared with CFA single treatment. The mRNA and protein expression of NLRP3, IL-1β, and IL-18 in TGs from trigeminal neuropathic pain mice were significantly inhibited by miR-186 mimics treatment compared to the CFA group. miR-186 was able to suppress the neuropathic pain via regulating the NLRP3 inflammasome signaling.

含吡呤结构域的NOD样受体家族成员3（NLRP3）炎性小体是中枢神经系统中研究最为频繁的炎性小体类型，且与神经病理性疼痛存在密切关联。本研究针对微小RNA（miR）-186通过调控完全弗氏佐剂（CFA）处理小鼠体内NLRP3的表达所介导的翻译后调控机制展开探究。研究采用CFA注射构建小鼠三叉神经病理性疼痛模型，通过三叉神经节（TGs）基因芯片检测开展相关分析。结果显示，相较于对照组，CFA处理组小鼠三叉神经节内NLRP3、白细胞介素（IL）-1β及IL-18的mRNA表达水平显著升高。此外，三叉神经病理性疼痛模型小鼠的三叉神经节中共筛选出26种差异表达的miRNA，其中miR-186的表达水平为所有差异miRNA中最低。进一步验证实验表明，NLRP3是miR-186的潜在靶基因。本研究向CFA处理小鼠注射miR-186模拟物，结果显示，与单纯CFA处理组相比，miR-186模拟物注射可显著提升模型小鼠的缩头阈值；同时，相较于CFA单独处理组，miR-186模拟物处理可显著抑制三叉神经病理性疼痛模型小鼠三叉神经节内NLRP3、IL-1β及IL-18的mRNA与蛋白表达水平。综上，miR-186可通过调控NLRP3炎性小体信号通路缓解神经病理性疼痛。