TY - JOUR
T1 - Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain
AU - Navia-Pelaez, Juliana M.
AU - Choi, Soo Ho
AU - dos Santos Aggum Capettini, Luciano
AU - Xia, Yining
AU - Gonen, Ayelet
AU - Agatisa-Boyle, Colin
AU - Delay, Lauriane
AU - dos Santos, Gilson Gonçalves
AU - Catroli, Glaucilene F.
AU - Kim, Jungsu
AU - Lu, Jenny W.
AU - Saylor, Benjamin
AU - Winkels, Holger
AU - Durant, Christopher P.
AU - Ghosheh, Yanal
AU - Beaton, Graham
AU - Ley, Klaus
AU - Kufareva, Irina
AU - Corr, Maripat
AU - Yaksh, Tony L.
AU - Miller, Yury I.
N1 - Publisher Copyright:
© 2021 Navia-Pelaez et al.
PY - 2021/5/10
Y1 - 2021/5/10
N2 - 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.
AB - 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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U2 - 10.1084/jem.20202059
DO - 10.1084/jem.20202059
M3 - Article
C2 - 33970188
AN - SCOPUS:85105716394
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
M1 - e20202059
ER -