miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis.
miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis.
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miRNA-23a/CXCR4通过直接靶向TXNIP/NLRP3炎性体轴调节神经性疼痛
DOI：
10.1186/s12974-018-1073-0
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发表时间：
2018-01-31
影响因子：
9.3
通讯作者：
Cheung CW
中科院分区：
文献类型：
--
作者：
Pan Z;Shan Q;Gu P;Wang XM;Tai LW;Sun M;Luo X;Sun L;Cheung CW
脊髓胶质细胞中的趋化因子CXC受体4 （CXCR4）与神经性疼痛有关。然而，CXCR4在神经性疼痛中的调节级联仍然是难以捉摸的。在这里，我们研究了mirna在疼痛过程中的功能调节作用及其与CXCR4及其下游信号传导的相互作用。方法采用部分坐骨神经结扎法（pSNL）对坐骨神经损伤小鼠脊髓进行smirna和CXCR4及其下游信号分子的检测。通过免疫印迹、免疫荧光、免疫沉淀、哺乳动物双杂交和行为实验来探索下游cxcr4依赖的信号通路。结果psnl致神经性疼痛小鼠脊髓胶质细胞中scxcr4表达升高。阻断CXCR4可减轻疼痛行为;相反，过表达CXCR4诱导疼痛超敏反应。MicroRNA-23a-3p （miR-23a）直接结合到CXCR4 mRNA的3 ' UTR上。psnl诱导的神经性疼痛显著降低miR-23a mRNA的表达。通过鞘内注射miR-23a模拟物或慢病毒过表达miR-23a，可减少脊髓CXCR4并预防psnl诱导的神经性疼痛。相比之下，鞘内注射miR-23a抑制剂或慢病毒敲低miR-23a可诱导疼痛样行为，这种行为可通过抑制CXCR4而减少。此外，naïve小鼠中miR-23a敲低或CXCR4过表达可增加硫氧还蛋白相互作用蛋白（TXNIP）， TXNIP与诱导nod样受体蛋白3 （NLRP3）炎性体相关。事实上，CXCR4和TXNIP共表达。哺乳动物双杂交实验揭示了CXCR4和TXNIP之间的直接相互作用，在pSNL小鼠脊髓中增加。特别是，TXNIP的抑制逆转了pSNL、miR-23a敲低或CXCR4过表达引起的疼痛行为。此外，miR-23a过表达或CXCR4敲低可抑制pSNL小鼠TXNIP和NLRP3炎性体的增加。结论smir -23a直接靶向CXCR4，通过脊髓胶质细胞的TXNIP/NLRP3炎性小体轴调控神经性疼痛。针对miR-23a、CXCR4或TXNIP的表观遗传干预可能作为治疗周围神经损伤引起的伤害性超敏反应的新治疗途径。
BackgroundChemokine CXC receptor 4 (CXCR4) in spinal glial cells has been implicated in neuropathic pain. However, the regulatory cascades of CXCR4 in neuropathic pain remain elusive. Here, we investigated the functional regulatory role of miRNAs in the pain process and its interplay with CXCR4 and its downstream signaling.MethodsmiRNAs and CXCR4 and its downstream signaling molecules were measured in the spinal cords of mice with sciatic nerve injury via partial sciatic nerve ligation (pSNL). Immunoblotting, immunofluorescence, immunoprecipitation, and mammal two-hybrid and behavioral tests were used to explore the downstream CXCR4-dependent signaling pathway.ResultsCXCR4 expression increased in spinal glial cells of mice with pSNL-induced neuropathic pain. Blocking CXCR4 alleviated the pain behavior; contrarily, overexpressing CXCR4 induced pain hypersensitivity. MicroRNA-23a-3p (miR-23a) directly bounds to 3′ UTR of CXCR4 mRNA. pSNL-induced neuropathic pain significantly reduced mRNA expression of miR-23a. Overexpression of miR-23a by intrathecal injection of miR-23a mimics or lentivirus reduced spinal CXCR4 and prevented pSNL-induced neuropathic pain. In contrast, knockdown of miR-23a by intrathecal injection of miR-23a inhibitor or lentivirus induced pain-like behavior, which was reduced by CXCR4 inhibition. Additionally, miR-23a knockdown or CXCR4 overexpression in naïve mice could increase the thioredoxin-interacting protein (TXNIP), which was associated with induction of NOD-like receptor protein 3 (NLRP3) inflammasome. Indeed, CXCR4 and TXNIP were co-expressed. The mammal two-hybrid assay revealed the direct interaction between CXCR4 and TXNIP, which was increased in the spinal cord of pSNL mice. In particular, inhibition of TXNIP reversed pain behavior elicited by pSNL, miR-23a knockdown, or CXCR4 overexpression. Moreover, miR-23a overexpression or CXCR4 knockdown inhibited the increase of TXNIP and NLRP3 inflammasome in pSNL mice.ConclusionsmiR-23a, by directly targeting CXCR4, regulates neuropathic pain via TXNIP/NLRP3 inflammasome axis in spinal glial cells. Epigenetic interventions against miR-23a, CXCR4, or TXNIP may potentially serve as novel therapeutic avenues in treating peripheral nerve injury-induced nociceptive hypersensitivity.
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影响因子：
11.1
作者：
Bali, Kiran Kumar;Selvaraj, Deepitha;Satagopam, Venkata P.;Lu, Jianning;Schneider, Reinhard;Kuner, Rohini
通讯作者：
Kuner, Rohini
星形胶质细胞中NLRP3炎症小体的解偶联蛋白2调节及其对抑郁症的影响
影响因子：
11.4
作者：
Du, Ren-Hong;Wu, Fang-Fang;Lu, Ming;Shu, Xiao-dong;Ding, Jian-Hua;Wu, Guangyu;Hu, Gang
通讯作者：
Hu, Gang
影响因子：
11.2
作者：
Hatzl S;Geiger O;Kuepper MK;Caraffini V;Seime T;Furlan T;Nussbaumer E;Wieser R;Pichler M;Scheideler M;Nowek K;Jongen-Lavrencic M;Quehenberger F;Wölfler A;Troppmair J;Sill H;Zebisch A
通讯作者：
Zebisch A
背根神经节和脊髓中趋化因子 CXCL12 的上调有助于大鼠神经损伤后神经病理性疼痛的发生和维持
影响因子：
5.6
作者：
Bai, Liying;Wang, Xinru;Xu, Ji-Tian
通讯作者：
Xu, Ji-Tian
影响因子：
3.7
作者：
Gustin A;Kirchmeyer M;Koncina E;Felten P;Losciuto S;Heurtaux T;Tardivel A;Heuschling P;Dostert C
通讯作者：
Dostert C