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Article: miRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis

TitlemiRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis
Authors
KeywordsmiRNA-23a
CXCR4
TXNIP
NLRP3 inflammasome
Sciatic nerve injury
Issue Date2018
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.jneuroinflammation.com/home/
Citation
Journal of Neuroinflammation, 2018, v. 15, p. article no. 29 How to Cite?
AbstractBackground: 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.
Persistent Identifierhttp://hdl.handle.net/10722/279443
ISSN
2018 Impact Factor: 5.7
2015 SCImago Journal Rankings: 2.538
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorPan, Z-
dc.contributor.authorShan, Q-
dc.contributor.authorGU, P-
dc.contributor.authorWang, XM-
dc.contributor.authorTai, LW-
dc.contributor.authorSun, M-
dc.contributor.authorLuo, X-
dc.contributor.authorSun, L-
dc.contributor.authorCheung, CW-
dc.date.accessioned2019-11-01T07:17:27Z-
dc.date.available2019-11-01T07:17:27Z-
dc.date.issued2018-
dc.identifier.citationJournal of Neuroinflammation, 2018, v. 15, p. article no. 29-
dc.identifier.issn1742-2094-
dc.identifier.urihttp://hdl.handle.net/10722/279443-
dc.description.abstractBackground: 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.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.jneuroinflammation.com/home/-
dc.relation.ispartofJournal of Neuroinflammation-
dc.rightsJournal of Neuroinflammation. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectmiRNA-23a-
dc.subjectCXCR4-
dc.subjectTXNIP-
dc.subjectNLRP3 inflammasome-
dc.subjectSciatic nerve injury-
dc.titlemiRNA-23a/CXCR4 regulates neuropathic pain via directly targeting TXNIP/NLRP3 inflammasome axis-
dc.typeArticle-
dc.identifier.emailWang, XM: xmwang1@hku.hk-
dc.identifier.emailCheung, CW: cheucw@hku.hk-
dc.identifier.authorityCheung, CW=rp00244-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12974-018-1073-0-
dc.identifier.pmid29386025-
dc.identifier.pmcidPMC5791181-
dc.identifier.scopuseid_2-s2.0-85041601237-
dc.identifier.hkuros308620-
dc.identifier.volume15-
dc.identifier.spagearticle no. 29-
dc.identifier.epagearticle no. 29-
dc.publisher.placeUnited Kingdom-

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