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 - Funding Information:
Disclosures: G. Beaton reported grants from University of California, San Diego, and Epigen Biosciences Inc. during the conduct of the study, and grants from RAFT Pharmaceuticals LLC outside the submitted work. K. Ley reported grants from NIH during the conduct of the study, and grants from Takeda and Novo Nordisk outside the submitted work. M. Corr reported "other" from Gilead outside the submitted work. T.L. Yaksh reported "other" from Raft Pharmaceuticals LLC outside the submitted work; in addition, T.L. Yaksh had a patent to US 10,729,788 B2 issued and is scientific co-founder of Raft Pharmaceuticals LLC. Y.I. Miller reported non-financial support from Raft Pharmaceuticals LLC outside the submitted work; in
Funding Information:
This study was supported by National Institutes of Health grants NS102432 (to Y.I. Miller and T.L. Yaksh), NS104769 (to Y.I. Miller and T.L. Yaksh), NS099338 (to T.L. Yaksh and M. Corr), HL135737 (to Y.I. Miller), HL136275 (to Y.I. Miller and K. Ley), and São Paulo Research Foundation grant FAPESP 2018/05778-3 (to G.F. Catroli). National Institute of Neurological Disorders and Stroke grant P30 NS047101 supports the University of California, San Diego, School of Medicine Microscopy Core. Author contributions: Studies were designed and planned by Y.I. Miller, S.-H. Choi, J.M. Navia-Pelaez, and T.L. Yaksh. The experiments were performed by J.M. Navia-Pelaez, S.-H. Choi, L.d.S.A. Capettini, A. Gonen, C. Agatisa-Boyle, L. Delay, B. Saylor, Y. Xia, G. Gonçalves dos Santos, G.F. Catroli, J.W. Lu, and J. Kim. The RNA-seq experiments were performed by J.M. Navia-Pelaez, H. Winkels, and C.P. Durant, analyzed by J.M. Navia-Pelaez and Y. Ghosheh, and supervised by K. Ley. Other data analyses were performed by J.M. Navia-Pelaez, S.-H. Choi, and Y.I. Miller; J.M. Navia-Pelaez and Y.I. Miller wrote the manuscript. T.L. Yaksh, M. Corr, S.-H. Choi, G. Beaton, and I. Kufareva contributed to study discussions and manuscript revisions.
Funding Information:
This study was supported by National Institutes of Health grants NS102432 (to Y.I. Miller and T.L. Yaksh), NS104769 (to Y.I. Miller and T.L. Yaksh), NS099338 (to T.L. Yaksh and M. Corr), HL135737 (to Y.I. Miller), HL136275 (to Y.I. Miller and K. Ley), and São Paulo Research Foundation grant FAPESP 2018/05778-3 (to G.F. Catroli). National Institute of Neurological Disorders and Stroke grant P30 NS047101 supports the University of California, San Diego, School of Medicine Microscopy Core.
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 -