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.
Center for Laboratory Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Neurochem Res. 2021 Feb;46(2):358-366. doi: 10.1007/s11064-020-03171-3. Epub 2020 Nov 16.
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 是一种氧化固醇调节的核转录因子，可促进胆固醇逆转运和替代（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痛觉过敏的发展加快，持续时间延长。此外，LXRα 基因敲除小鼠坐骨神经中 M1 样巨噬细胞标志物诱导型一氧化氮合酶（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，LXRs 激动剂 GW3965 在神经挤压后立即给予野生型小鼠坐骨神经周围，可抑制挤压损伤引起的机械性痛觉过敏。GW3965 还抑制损伤神经中 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 中和抗体可阻止 GW3965 对机械性痛觉过敏的缓解作用。总之，这些结果表明，坐骨神经中缺乏 LXRα 会导致巨噬细胞的炎症表型增强，从而加速神经性疼痛的发展，并抑制神经损伤后的恢复。其激动剂激活 LXRα 可能会重新平衡神经保护和神经毒性巨噬细胞表型，从而缓解神经性疼痛行为。
