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.

周围神经损伤常常导致神经性疼痛。在本研究中，我们评估了肝 x 受体 α (LXRα) 在神经性疼痛发展中的作用，LXRα 是一种氧甾醇调节的核转录因子，可促进胆固醇反向转运和替代性 (M2) 巨噬细胞激活。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生加速且持续时间延长。此外，M1样巨噬细胞标记物iNOS和M1样巨噬细胞诱导剂过氧化氢（H2O2）的表达增加，而M2巨噬细胞标记物精氨酸酶1（Arg-1）和白细胞介素10（IL-10）的表达减少LXRα 敲除小鼠的坐骨神经。此外，神经挤压后立即对野生型小鼠进行坐骨神经周围注射 LXR 激动剂 GW3965，抑制了挤压损伤引起的机械异常性疼痛。 GW3965 还抑制受损神经中 iNOS 的表达和 H2O2 的产生，并增强 IL-10 和 Arg-1 的表达。重要的是，坐骨神经周围给予IL-10中和抗体阻止了GW3965对机械异常性疼痛的缓解作用。总而言之，这些结果表明，坐骨神经中缺乏 LXRα 会导致巨噬细胞炎症反应增强，最终加速神经性疼痛的发展并抑制神经损伤后的恢复。 LXRα 的激动剂激活可能会重新平衡神经保护性和神经毒性巨噬细胞表型，从而减轻神经性疼痛行为。