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Papers of the Week

Papers: 8 May 2021 - 14 May 2021

Animal Studies

2021 Jul 05

J Exp Med



Editor's Pick

Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain.


Navia-Pelaez JM, Choi S-H, Dos Santos Aggum Capettini L, Xia Y, Gonen A, Agatisa-Boyle C, Delay L, Dos Santos G 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, et al.
J Exp Med. 2021 Jul 05; 218(7).
PMID: 33970188.


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.