Liver X Receptor alpha in Sciatic Nerve Exerts an Alleviating Effect on Neuropathic Pain Behaviors Induced by Crush Injury
Liver X Receptor alpha in Sciatic Nerve Exerts an Alleviating Effect on Neuropathic Pain Behaviors Induced by Crush Injury
复制标题
坐骨神经中的肝脏 X 受体 α 对挤压伤引起的神经性疼痛行为有缓解作用
DOI：
10.1007/s11064-020-03171-3
复制
发表时间：
2021
影响因子：
4.4
通讯作者：
Wei Xuhong
中科院分区：
文献类型：
--
作者：
Mao Zuchao;Huang Ruizhen;Xu Jing;Guo Ruixian;Wei Xuhong
周围神经损伤常导致神经性疼痛。在本研究中，我们评估了肝脏x受体α（LXRα）在神经性疼痛发展中的作用，LXR α是一种氧化固醇调节的核转录因子，可促进胆固醇逆向转运和替代（M2）巨噬细胞活化。我们发现，与WT小鼠相比，在LXRα基因敲除小鼠中，坐骨神经挤压后机械性异常性疼痛的发展加速，持续时间延长。此外，在LXRα基因敲除小鼠的坐骨神经中，M1样巨噬细胞标志物iNOS和M1样巨噬细胞诱导剂过氧化氢（H2 O2）的表达增加，而M2巨噬细胞标志物精氨酸酶-1（Arg-1）和白细胞介素-10（IL-10）的表达减少。此外，在神经挤压后立即向野生型小鼠坐骨周施用LXR激动剂GW 3965，抑制了挤压损伤诱导的机械性异常性疼痛。GW 3965还可抑制损伤神经中iNOS的表达和H2 O2的产生，并增强IL-10和Arg-1的表达。重要的是，坐骨周施用IL-10中和抗体阻止了GW 3965对机械性异常性疼痛的缓解作用。总之，这些结果表明，坐骨神经中缺乏LXRα导致巨噬细胞的炎症特征增强，最终加速神经性疼痛的发展并抑制其在神经损伤后的恢复。LXRα的激动剂激活LXRα可能会重新平衡神经保护和神经毒性巨噬细胞表型，从而减轻神经病理性疼痛行为。
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.