학술논문
Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain
Document Type
article
Author
Navia-Pelaez, Juliana M; Choi, Soo-Ho; dos Santos Aggum Capettini, Luciano; Xia, Yining; Gonen, Ayelet; Agatisa-Boyle, Colin; Delay, Lauriane; dos Santos, Gilson Gonçalves; Catroli, Glaucilene F; Kim, Jungsu; Lu, Jenny W; Saylor, Benjamin; Winkels, Holger; Durant, Christopher P; Ghosheh, Yanal; Beaton, Graham; Ley, Klaus; Kufareva, Irina; Corr, Maripat; Yaksh, Tony L; Miller, Yury I
Source
Journal of Experimental Medicine. 218(7)
Subject
Language
Abstract
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.