Department of Medicine, University of California, San Diego, La Jolla, CA.
Department of Anesthesiology, University of California, San Diego, La Jolla, CA.
J Exp Med. 2021 Jul 5;218(7). doi: 10.1084/jem.20202059. Epub 2021 May 10.
Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naive mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia or reverse CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling the TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.
神经炎症是向神经性疼痛状态转变和持续存在的主要因素。脊髓神经炎症涉及 TLR4 的激活，该受体定位于增大的富含胆固醇的脂筏，即炎性脂筏。小胶质细胞中胆固醇转运蛋白 ABCA1 和 ABCG1 的条件性缺失导致炎性脂筏形成，导致未处理的小鼠出现触觉过敏。载脂蛋白 A-I 结合蛋白 (AIBP) 可促进炎性脂筏中的胆固醇耗竭，并在野生型小鼠化疗诱导的周围神经病变 (CIPN) 模型中逆转神经性疼痛，但 AIBP 未能在 ABCA1/ABCG1 缺陷型小胶质细胞的小鼠中逆转触觉过敏，表明存在胆固醇依赖性机制。缺乏 TLR4 结合域的 AIBP 突变体不能与小胶质细胞结合或逆转 CIPN 触觉过敏。单次 AIBP 剂量在 CIPN 中的持久治疗效果与抗炎和胆固醇代谢重编程以及小胶质细胞中脂质滴的积累减少有关。这些结果表明，通过控制小胶质细胞中 TLR4 炎性脂筏和基因表达程序，以及阻断神经炎症的持续存在，胆固醇驱动了神经性疼痛的调节机制。
