Normalization of Cholesterol Metabolism in Spinal Microglia Alleviates Neuropathic Pain

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2021 May 10

PMID 33970188

Citations 39

Authors

Juliana M Navia-Pelaez

Soo-Ho Choi

Luciano Dos Santos Aggum Capettini

Yining Xia

Ayelet Gonen

Colin Agatisa-Boyle

Lauriane Delay

Gilson Goncalves Dos Santos

Glaucilene F Catroli

Jungsu Kim

Jenny W Lu

Benjamin Saylor

Holger Winkels

Christopher P Durant

Yanal Ghosheh

Graham Beaton

Klaus Ley

Irina Kufareva

Maripat Corr

Tony L Yaksh

Yury I Miller

Affiliations

Soon will be listed here.

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.

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