Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain.
Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain.
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脊髓小胶质细胞胆固醇代谢正常化可减轻神经性疼痛。
DOI：
10.1084/jem.20202059
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发表时间：
2021-07-05
期刊：
影响因子：
--
通讯作者：
Miller YI
中科院分区：
文献类型：
--
作者：
Navia-Pelaez JM;Choi SH;Dos Santos Aggum Capettini L;Xia Y;Gonen A;Agatisa-Boyle C;Delay L;Gonçalves Dos Santos G;Catroli GF;Kim J;Lu JW;Saylor B;Winkels H;Durant CP;Ghosheh Y;Beaton G;Ley K;Kufareva I;Corr M;Yaksh TL;Miller YI
在化疗诱导的周围神经病变的小鼠模型中，脊髓小胶质细胞的特征在于存在炎性筏-增大的、富含胆固醇的脂质筏-其组织炎症反应。对调节胆固醇代谢的特定机制的操纵使炎性脂肪正常化并重新编程小胶质细胞，从而导致神经性疼痛的长期缓解。神经炎症是神经病理性疼痛状态转变和持续的主要组成部分。脊髓神经炎症涉及TLR 4的激活，定位于扩大的富含胆固醇的脂筏，在此称为炎性脂筏。条件性删除小胶质细胞中的胆固醇转运蛋白ABCA 1和ABCG 1，导致炎症形成，诱导幼稚小鼠的触觉异常性疼痛。apoA-I结合蛋白（AIBP）促进炎症因子中胆固醇的消耗，并逆转野生型小鼠化疗诱导的周围神经病变（CIPN）模型中的神经性疼痛，但AIBP未能逆转ABCA 1/ABCG 1缺陷型小胶质细胞小鼠的异常性疼痛，这表明胆固醇依赖性机制。缺乏TLR 4结合结构域的AIBP突变体不结合小胶质细胞或逆转CIPN异常性疼痛。CIPN中单次AIBP剂量的持久治疗效果与抗炎和胆固醇代谢重编程以及减少小胶质细胞中脂滴的积累有关。这些结果表明，胆固醇驱动的调节神经性疼痛的机制，通过控制TLR 4 inflamarafts和小胶质细胞中的基因表达程序，并阻止神经炎症的永久化。
In a mouse model of chemotherapy-induced peripheral neuropathy, spinal microglia are characterized by the presence of inflammarafts—enlarged, cholesterol-enriched lipid rafts—which organize the inflammatory response. Manipulation of specific mechanisms regulating cholesterol metabolism normalizes inflammarafts and reprograms microglia, resulting in long-lasting alleviation of neuropathic pain. 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.
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