Abstract
Neuropathic pain is a somatosensory nervous system dysfunction that remains a threatening health problem globally. Recent studies have highlighted the involvement of C-C motif chemokine receptor 1 (CCR1) in neuropathic pain. Herein, the current study set out to explore the modulatory role of CCR1 in spinal nerve ligation (SNL)-induced neuropathic pain and its underlying molecular mechanism. First, it was found that CCR1 was highly expressed in spinal cord tissues and microglial cells of SNL rats. On the other hand, CCR1 knockdown attenuated nerve pain in SNL rats and repressed microglial cell activation in SNL rats and also in the LPS-induced microglial cell model of nerve injury, as evidenced by elevated microglial cell markers OX-42 and IL-1β, IL-6 and TNF-α. Mechanistically, CCR1 enhanced small ubiquitin-like modifier 1 (SUMO1) modification of DiGeorge syndrome critical region gene 8 (DGCR8) in LPS-treated microglial cells by phosphorylating ERK. Moreover, CCR1 silencing brought about elevations in mechanical withdrawal threshold and thermal withdrawal latency. To conclude, our findings indicated that CCR1 enhanced the modification of DGCR8 by SUMO1 through phosphorylation of ERK, thereby promoting the activation and inflammatory response of spinal cord microglial cells and increasing the sensitivity of SNL rats to pain. Thus, this study offers a promising therapeutic target for the management of neuropathic pain.
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The research was supported by Project supported by the National Natural Science Foundation of China (Grant No. 82002387).
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CXS, JJ, YGX and ZL designed the study. JHM and TL were involved in data collection and statistical analysis. HYX and ZL prepared the figures. CXS, JJ, HYX and YGX drafted the paper. All authors read and approved the final manuscript.
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Shi, C., Jin, J., Xu, H. et al. CCR1 enhances SUMOylation of DGCR8 by up-regulating ERK phosphorylation to promote spinal nerve ligation-induced neuropathic pain. Gene Ther 29, 379–389 (2022). https://doi.org/10.1038/s41434-021-00285-3
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DOI: https://doi.org/10.1038/s41434-021-00285-3