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Liver X Receptor α in Sciatic Nerve Exerts an Alleviating Effect on Neuropathic Pain Behaviors Induced by Crush Injury

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Abstract

Peripheral nerve injury often leads to neuropathic pain. In the present study, we assessed the role of liver x receptor alpha (LXRα), an oxysterol regulated nuclear transcription factor that promotes reverse cholesterol transport and alternative (M2) macrophage activation, in the development of neuropathic pain. We found that compared to WT mice, in LXRα knockout mice the development of mechanical allodynia following sciatic nerve crush was accelerated and the duration was prolonged. Furthermore, the expression of M1-like macrophage marker iNOS and M1-like macrophages inducer hydrogen peroxide (H2O2) was increased, whereas expression of M2 macrophage marker arginase-1 (Arg-1) and interleukin-10 (IL-10) was reduced in the sciatic nerve of LXRα knockout mice. Moreover, peri-sciatic administration of LXRs agonist GW3965, immediately after the nerve crush, into wild type mice, suppressed the mechanical allodynia induced by crush injury. GW3965 also suppressed the expression of iNOS and production of H2O2 in the injured nerve and enhanced the expression of IL-10 and Arg-1. Importantly, peri-sciatic administration of IL-10 neutralization antibody prevented the alleviating effect of GW3965 on mechanical allodynia. Altogether, these results indicates that the lack of LXRα in the sciatic nerve results in an augmented inflammatory profile of macrophages, which ultimately speed up the development of neuropathic pain and dampen its recovery following nerve injury. Activation of LXRα by its agonist might rebalance the neuroprotective and neurotoxic macrophage phenotypes, and thus alleviate the neuropathic pain behavior.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Beijing, People’s Republic of China. Nos. 81870969, 81471250); Nature Science Foundation of Guangdong Province of China (Guangzhou, People’s Republic of China, No. 2019A1515011855).

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  1. Zuchao Mao and Ruizhen Huang have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, Guangdong, People’s Republic of China

    Zuchao Mao, Ruizhen Huang, Jing Xu, Ruixian Guo & Xuhong Wei

  2. Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, People’s Republic of China

    Xuhong Wei

  3. Center for Laboratory Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, China

    Jing Xu

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  1. Zuchao Mao
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Mao, Z., Huang, R., Xu, J. et al. Liver X Receptor α in Sciatic Nerve Exerts an Alleviating Effect on Neuropathic Pain Behaviors Induced by Crush Injury. Neurochem Res 46, 358–366 (2021). https://doi.org/10.1007/s11064-020-03171-3

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