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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Neuroinflammation 1/2018

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

Zeitschrift:
Journal of Neuroinflammation > Ausgabe 1/2018
Autoren:
Zhiqiang Pan, Qun Shan, Pan Gu, Xiao Min Wang, Lydia Wai Tai, Menglan Sun, Xin Luo, Liting Sun, Chi Wai Cheung
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12974-018-1073-0) contains supplementary material, which is available to authorized users.

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.
Zusatzmaterial
Additional file 1: Figure S1. The CXCR4 mRNA expression in spinal cell types. a–c Combined FISH of CXCR4 mRNA (green) and immunofluorescence staining of NeuN (a), GFAP (b), or IBA1 (c) (red) in the ipsilateral spinal cord of normal mice. The antisense probe of CXCR4 mRNA and marker protein antibodies were hybridized to the spinal cord slice of normal mice. Scale bar, 50 μm. Arrows indicate the positive CXCR4 mRNA signal. Figure S2. The TXNIP mRNA expression in spinal cell types. a–c Combined FISH of CXCR4 mRNA (green) and immunofluorescence staining of NeuN (a), GFAP (b), or IBA1 (c) (red) in ipsilateral spinal cord of normal mice. The antisense probe of TXNIP mRNA and marker protein antibodies were hybridized to the spinal cord slice of normal mice. Scale bar, 50 μm. Arrows indicate the positive TXNIP mRNA signal. Figure S3. The knockdown validation of TXNIP siRNA-681 and siRNA-1271 in vivo. a–b TXNIP mRNA (a) and protein (b) change after intrathecal injection of TXNIP siRNA. The scrambled or siRNAs were daily intrathecally injected for 3 consecutive days in normal mice, and spinal cord was harvested at 48 h after last injection, p < 0.01. Data are presented as mean ± SEM; **p < 0.01 versus Scr group; n = 5. (PPTX 2670 kb)
12974_2018_1073_MOESM1_ESM.pptx
Literatur
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