Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain

Juliana M. Navia-Pelaez, Soo Ho Choi, Luciano dos Santos Aggum Capettini, Yining Xia, Ayelet Gonen, Colin Agatisa-Boyle, Lauriane Delay, Gilson Gonçalves 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. YakshYury I. Miller

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish (US)
Article numbere20202059
JournalJournal of Experimental Medicine
Issue number7
StatePublished - May 10 2021
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)


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