miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis
Abstract Background Chemokine 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...
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doaj-577869b187dc46ce90deb0102b8914c82020-11-25T01:43:16ZengBMCJournal of Neuroinflammation1742-20942018-01-0115111910.1186/s12974-018-1073-0miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axisZhiqiang Pan0Qun Shan1Pan Gu2Xiao Min Wang3Lydia Wai Tai4Menglan Sun5Xin Luo6Liting Sun7Chi Wai Cheung8Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical UniversityLaboratory and Clinical Research Institute for Pain, Department of Anesthesiology, The University of Hong KongLaboratory and Clinical Research Institute for Pain, Department of Anesthesiology, The University of Hong KongLaboratory and Clinical Research Institute for Pain, Department of Anesthesiology, The University of Hong KongLaboratory and Clinical Research Institute for Pain, Department of Anesthesiology, The University of Hong KongJiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical UniversityLaboratory and Clinical Research Institute for Pain, Department of Anesthesiology, The University of Hong KongLaboratory and Clinical Research Institute for Pain, Department of Anesthesiology, The University of Hong KongLaboratory and Clinical Research Institute for Pain, Department of Anesthesiology, The University of Hong KongAbstract Background Chemokine 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. Methods miRNAs 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. Results CXCR4 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. Conclusions miR-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.http://link.springer.com/article/10.1186/s12974-018-1073-0miRNA-23aCXCR4TXNIPNLRP3 inflammasomeSciatic nerve injurySpinal glia cell |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhiqiang Pan Qun Shan Pan Gu Xiao Min Wang Lydia Wai Tai Menglan Sun Xin Luo Liting Sun Chi Wai Cheung |
spellingShingle |
Zhiqiang Pan Qun Shan Pan Gu Xiao Min Wang Lydia Wai Tai Menglan Sun Xin Luo Liting Sun Chi Wai Cheung miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis Journal of Neuroinflammation miRNA-23a CXCR4 TXNIP NLRP3 inflammasome Sciatic nerve injury Spinal glia cell |
author_facet |
Zhiqiang Pan Qun Shan Pan Gu Xiao Min Wang Lydia Wai Tai Menglan Sun Xin Luo Liting Sun Chi Wai Cheung |
author_sort |
Zhiqiang Pan |
title |
miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis |
title_short |
miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis |
title_full |
miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis |
title_fullStr |
miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis |
title_full_unstemmed |
miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis |
title_sort |
mirna-23a/cxcr4 regulates neuropathic pain via directly targeting txnip/nlrp3 inflammasome axis |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2018-01-01 |
description |
Abstract Background Chemokine 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. Methods miRNAs 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. Results CXCR4 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. Conclusions miR-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. |
topic |
miRNA-23a CXCR4 TXNIP NLRP3 inflammasome Sciatic nerve injury Spinal glia cell |
url |
http://link.springer.com/article/10.1186/s12974-018-1073-0 |
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