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Epigenetic Up-Regulation of ADAMTS4 in Sympathetic Ganglia is Involved in the Maintenance of Neuropathic Pain Following Nerve Injury

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Abstract

Sympathetic axonal sprouting into dorsal root ganglia is a major phenomenon implicated in neuropathic pain, and sympathetic ganglia blockage may relieve some intractable chronic pain in animal pain models and clinical conditions. These suggest that sympathetic ganglia participated in the maintenance of chronic pain. However, the molecular mechanism underlying sympathetic ganglia-mediated chronic pain is not clear. Here, we found that spared nerve injury treatment upregulated the expression of ADAMTS4 and AP-2α protein and mRNA in the noradrenergic neurons of sympathetic ganglia during neuropathic pain maintenance. Knockdown the ADAMTS4 or AP-2α by injecting specific retro scAAV-TH (Tyrosine Hydroxylase)-shRNA ameliorated the mechanical allodynia induced by spared nerve injury on day 21 and 28. Furthermore, chromatin immunoprecipitation and coimmunoprecipitation assays found that spared nerve injury increased the recruitment of AP-2α to the ADAMTS4 gene promoter, the interaction between AP-2α and histone acetyltransferase p300 and the histone H4 acetylation on day 28. Finally, knockdown the AP-2α reduced the acetylation of H4 on the promoter region of ADAMTS4 gene and suppressed the increase of ADAMTS4 expression induced by spared nerve injury. Together, these results suggested that the enhanced interaction between AP-2α and p300 mediated the epigenetic upregulation of ADAMTS4 in sympathetic ganglia noradrenergic neurons, which contributed to the maintenance of spared nerve injury induced neuropathic pain.

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Data Availability

The datasets analyzed during the current study are not publicly available since another ongoing study still using certain data but are available from the corresponding author on reasonable request.

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Acknowledgements

This study was funded by National Natural Science Foundation of China (Grant No. 31970936, 81870829, 82071224, 62175263), Natural Science Foundation of Guangdong (2019A1515010871, 2019A1515011447, 2022A1515012259), Guangzhou Science and Technology Plan Project (202206060004, 202002020011), Major Project of Basic and Applied Basic Research Foundation of Guangdong Province (2019B1515120054).

Funding

This study was funded by National Natural Science Foundation of China (Grant No.31970936, 81870829, 82071224, 62175263), Natural Science Foundation of Guangdong (2019A1515010871, 2019A1515011447, 2022A1515012259), Guangzhou Science and Technology Plan Project (202206060004, 202002020011), Major Project of Basic and Applied Basic Research Foundation of Guangdong Province (2019B1515120054).

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  1. Chen Wang and Ming Wei have contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Chen Wang, Ming Wei, Yan Wu, Hai-Ting Fan, Zheng-Kai Liang, An-Ran Liu & Xia Feng

  2. Zhongshan School of Medicine and Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou, 510080, China

    Wen-Jun Xin

  3. Department of Anesthesiology, The First Affiliated Hospital, 58 Zhong Shan Rd 2, Guangzhou, 510080, China

    Xia Feng

  4. Zhongshan Medical School, Sun Yat-sen University, Zhongshan Rd. 2, Guangzhou, China

    Wen-Jun Xin

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Contributions

XF and W-JX contributed to the study conception and design. Data collection and analysis were performed by CW and MW. The first draft of the manuscript was written by CW and MW. Material preparation were performed by YW. Experiments were performed by H-TF, Zheng-Kai Liang and A-RL. all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wen-Jun Xin or Xia Feng.

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The experimental protocols were approved by the Animal Care and Use Committee of Sun Yat-sen University and conducted in strict accordance with the guideline of National Institutes of Health on the animal care and the ethical guideline.

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Wang, C., Wei, M., Wu, Y. et al. Epigenetic Up-Regulation of ADAMTS4 in Sympathetic Ganglia is Involved in the Maintenance of Neuropathic Pain Following Nerve Injury. Neurochem Res 48, 2350–2359 (2023). https://doi.org/10.1007/s11064-023-03896-x

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