Open AccessNormalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain
Author(s) -
Juliana Maria Navia-Pelaez,
Soo–Ho Choi,
Luciano dos Santos Aggum Capettini,
Yining Xia,
Ayelet Gonen,
Colin Agatisa-Boyle,
Lauriane Delay,
Gilson Gonçalves dos Santos,
Glaucilene Ferreira Catroli,
Jung-Su Kim,
Jenny W Lu,
Benjamin P. Saylor,
Holger Winkels,
Christopher P. Durant,
Yanal Ghosheh,
Graham Beaton,
Klaus Ley,
Irina Kufareva,
Maripat Corr,
Tony L. Yaksh,
Yury I. Miller
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20202059
Subject(s) - microglia , neuroinflammation , neuropathic pain , allodynia , medicine , tlr4 , abca1 , trem2 , pharmacology , chemistry , hyperalgesia , immunology , receptor , inflammation , nociception , biochemistry , transporter , gene
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.