Hullugundi Swathi K, Dolkas Jennifer, Chernov Andrei V, Yaksh Tony L, Eddinger Kelly A, Angert Mila, Catroli Glaucilene Ferreira, Strongin Alex Y, Dougherty Patrick M, Li Yan, Quehenberger Oswal, Armando Aaron, Shubayev Veronica I
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA.
VA San Diego Healthcare System, La Jolla, CA, USA.
Brain Behav Immun Health. 2024 Mar 30;38:100757. doi: 10.1016/j.bbih.2024.100757. eCollection 2024 Jul.
A bioactive myelin basic protein (MBP) fragment, comprising MBP, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling.
In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP interactors by mass spectrometry of MBP pull-down; and (iii) liver X receptor (LXR)α protein expression by immunoblotting. To test the effect of LXRα stimulation on IN MBP-induced mechanical hypersensitivity, the LXRα expression was confirmed along the segmental neuraxis, in DRG and spinal cord, followed by von Frey testing of the effect of intrathecally administered synthetic LXR agonist, GW3965. In cultured male and female rat DRGs exposed to MBP and/or estrogen treatments, transcriptional effect of LXR stimulation by GW3965 was assessed on downstream cholesterol transporter Abc, interleukin (IL)-6, and pronociceptive Cacna2d1 gene expression.
CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP interacted with nuclear receptor coactivator (Ncoa)1, known to activate LXRα, injury-specific in nerves of both sexes. LXR stimulation suppressed ESR1-induced IL-6 and Cacna2d1 expression in cultured DRGs of both sexes and attenuated MBP-induced pain in females.
The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.
一种包含髓鞘碱性蛋白（MBP）的生物活性MBP片段在坐骨神经慢性压迫损伤（CCI）后释放。在完整的坐骨神经内注射（IN）MBP足以通过注射部位、同侧背根神经节（DRG）和脊髓的强大转录重塑诱导持续性神经性疼痛样行为。MBP的性别（雌性）特异性促伤害感受活性与胆固醇代谢的性别特异性变化以及雌激素受体（ESR）1信号通路的激活有关。
在雄性和雌性正常及CCI后的大鼠坐骨神经中，我们评估了：（i）通过脂质组学分析胆固醇前体和代谢物水平；（ii）通过MBP下拉质谱分析MBP相互作用蛋白；（iii）通过免疫印迹分析肝X受体（LXR）α蛋白表达。为了测试LXRα刺激对IN MBP诱导的机械性超敏反应的影响，先在DRG和脊髓的节段神经轴上确认LXRα的表达，然后通过von Frey测试鞘内注射合成LXR激动剂GW3965的效果。在暴露于MBP和/或雌激素处理的培养雄性和雌性大鼠DRG中，评估GW3965刺激LXR对下游胆固醇转运蛋白Abc、白细胞介素（IL）-6和促伤害感受基因Cacna2d1表达的转录作用。
CCI调节了两性神经中LXRα配体和受体水平，雌性相对于雄性，胆固醇前体、羊毛甾醇和7-脱氢胆固醇以及氧化甾醇升高。MBP与已知可激活LXRα的核受体辅激活因子（Ncoa）1相互作用，在两性神经中具有损伤特异性。LXR刺激抑制了两性培养DRG中ESR1诱导的IL-6和Cacna2d1表达，并减轻了雌性中MBP诱导的疼痛。
损伤释放的生物活性MBP片段通过选择性失活包括LXRα在内的核转录因子诱导促伤害感受变化。通过隔离Ncoa1，生物活性MBP片段使LXRα发挥功能，以抵消感觉神经元中雌激素/ESR1的促伤害感受活性。由于雌性相对于雄性循环雌激素水平较高，MBP片段的这种作用在雌性中更为普遍。恢复LXR活性是治疗生物活性MBP诱导的神经性疼痛的一种有前景的治疗策略。
