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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain

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Author(s):
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Navia-Pelaez, Juliana M. [1] ; Choi, Soo-Ho [1] ; Capettini, Luciano dos Santos Aggum [1] ; Xia, Yining [1] ; Gonen, Ayelet [1] ; Agatisa-Boyle, Colin [1] ; Delay, Lauriane [2] ; dos Santos, Gilson Goncalves [2] ; Catroli, Glaucilene F. [2] ; Kim, Jungsu [1] ; Lu, Jenny W. [1] ; Saylor, Benjamin [1] ; Winkels, Holger [3] ; Durant, Christopher P. [3] ; Ghosheh, Yanal [3] ; Beaton, Graham [4] ; Ley, Klaus [3] ; Kufareva, Irina [5] ; Corr, Maripat [1] ; Yaksh, Tony L. [2] ; Miller, I, Yury
Total Authors: 21
Affiliation:
[1] I, Univ Calif San Diego, Dept Med, La Jolla, CA 92093 - USA
[2] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 - USA
[3] La Jolla Inst Immunol, La Jolla, CA - USA
[4] Raft Pharmaceut, San Diego, CA - USA
[5] Univ Calif San Diego, Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 - USA
Total Affiliations: 5
Document type: Journal article
Source: JOURNAL OF EXPERIMENTAL MEDICINE; v. 218, n. 7 JUL 5 2021.
Web of Science Citations: 0
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 longlasting 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. (AU)

FAPESP's process: 18/05778-3 - The role of purinergic receptor P2X4 signaling of dorsal root ganglia and spinal cord in early and late phase allodynia in the K/BxN mouse model of chronic inflammation.
Grantee:Glaucilene Ferreira Catroli
Support Opportunities: Scholarships abroad - Research Internship - Doctorate