Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain

Autor(es):Mostrar menos -

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

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF EXPERIMENTAL MEDICINE; v. 218, n. 7 JUL 5 2021.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 18/05778-3 - O papel da sinalização do receptor purinérgico P2X4 dos gânglios da raiz dorsal e da medula espinhal na alodinia inicial e tardia no modelo de inflamação crônica em camundongos K/BxN
• Beneficiário: Glaucilene Ferreira Catroli
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado