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Up-regulation of CX3CL1 via Nuclear Factor-κB-dependent Histone Acetylation Is Involved in Paclitaxel-induced
Dai Li1, Zhen-Zhen Huang, Yun-Zhi Ling
1From Department of Physiology and Pain Research Center (D.L., Z.-Z.H., Y.-Z.L., J.-Y.W., Y.C., H.-Q.Z., W.-J.X.), Zhongshan Medical School, and Department of Hematology (X.-Z.Z.), the Third Affiliated Hospital, Sun Yet-Sen University, Guangzhou, Guangdong, People's Republic of China.
Background:
Up-regulation of CX3CL1 has been revealed to be involved in the neuropathic pain induced by nerve injury. However, whether CX3CL1 participates in the paclitaxel-induced painful peripheral neuropathy remains unknown. The aim of the current study was to elucidate the involvement of transcriptional factors nuclear factor-κB (NF-κB) and its causal interaction with CX3CL1 signaling in the paclitaxel-induced painful peripheral neuropathy.
Methods:
Painful peripheral neuropathy induced by paclitaxel treatment was established in adult male Sprague-Dawley rats. The von Frey test were performed to evaluate neuropathic pain behavior, and real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were performed to understand the molecular mechanisms.
Results:
The application of paclitaxel induced an up-regulation of CX3CL1 expression in the spinal neurons, which is reduced significantly by NF-κB inhibitor ammonium pyrrolidinedithiocarbamate or p65 small interfering RNA. Blockade of either CX3CL1 (n = 12 each) or NF-κB (n = 12 each) signaling pathway attenuated mechanical allodynia induced by paclitaxel. Chromatin immunoprecipitation further found that paclitaxel induced an increased recruitment of nuclear factor-κB (NF-κB)p65 to the Cx3cl1 promoter region. Furthermore, an increased acetylation level of H4, but not H3, in Cx3cl1 promoter region in spinal neurons was detected after paclitaxel treatment, which was reversed by inhibition of NF-κB with ammonium pyrrolidinedithiocarbamate or p65 small interfering RNA.
Conclusions:
These findings suggest that up-regulation of CX3CL1 via NF-κB-dependent H4 acetylation might be critical for paclitaxel-induced mechanical allodynia.
Insights
Paclitaxel causes painful neuropathy by increasing CX3CL1 through NF-κB signaling and H4 acetylation. Inhibiting this pathway alleviates pain, suggesting a therapeutic target for chemotherapy-induced peripheral neuropathy.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Chemotherapy drug paclitaxel can cause painful peripheral neuropathy.
- CX3CL1 signaling is implicated in nerve injury pain.
- The role of CX3CL1 in paclitaxel-induced neuropathy is unknown.
Purpose of the Study:
- To investigate the involvement of nuclear factor-κB (NF-κB) and CX3CL1 signaling in paclitaxel-induced painful peripheral neuropathy.
- To elucidate the interaction between NF-κB and CX3CL1 in this condition.
Main Methods:
- Paclitaxel-induced neuropathy model in Sprague-Dawley rats.
- Behavioral assessment using the von Frey test.
- Molecular analyses including qPCR, Western blot, ChIP, and siRNA.
Main Results:
- Paclitaxel increased spinal CX3CL1 expression, which was reduced by NF-κB inhibition.
- Blocking CX3CL1 or NF-κB attenuated paclitaxel-induced mechanical allodynia.
- NF-κB (p65) binding to the Cx3cl1 promoter and H4 acetylation increased after paclitaxel treatment, reversed by NF-κB inhibition.
Conclusions:
- Paclitaxel-induced mechanical allodynia involves CX3CL1 up-regulation.
- NF-κB-dependent H4 acetylation at the Cx3cl1 promoter is a key mechanism.
- This pathway represents a potential therapeutic target for chemotherapy-induced neuropathic pain.
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