ApoA-I binding protein (AIBP) regulates transient receptor potential vanilloid 1 (TRPV1) activity in rat dorsal root ganglion neurons by selective disruption of toll-like receptor 4 (TLR4)-lipid rafts

•Male and female TLR4 mis-sense rats do not develop behavioral signs of paclitaxel CIPN.•DRG neurons in TLR4 mis-sense rats are not hyperexcitable following paclitaxel.•DRG neurons from TLR4 mis-sense rats show reduced capsaicin-evoked calcium influx.•TLR4 mis-sense affects the function of TRPV1, bu...

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Published in:Brain, behavior, and immunity behavior, and immunity, 2025-01, Vol.123, p.644-655
Main Authors: Li, Yan, Uhelski, Megan L., North, Robert Y., Farson, Luke B., Bankston, Christopher B., Roland, Gavin H., Fan, Dwight H., Sheffield, Katherine N., Jia, Amy, Orlando, Dana, Heles, Mario, Yaksh, Tony L., Miller, Yury I., Kosten, Therese A., Dougherty, Patrick M.
Format: Article
Language:English
Subjects:
Animals
Calcium imaging
Chemotherapy
Female
Ganglia, Spinal - metabolism
Male
Membrane Microdomains - metabolism
Neurons - metabolism
Neuropathy
Paclitaxel
Paclitaxel - pharmacology
Rats
Rats, Sprague-Dawley
TLR4 mis-sense
Toll-Like Receptor 4 - metabolism
TRPV Cation Channels - metabolism
Whole-cell recording
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Summary:•Male and female TLR4 mis-sense rats do not develop behavioral signs of paclitaxel CIPN.•DRG neurons in TLR4 mis-sense rats are not hyperexcitable following paclitaxel.•DRG neurons from TLR4 mis-sense rats show reduced capsaicin-evoked calcium influx.•TLR4 mis-sense affects the function of TRPV1, but not its overall expression.•Alteration of lipid rafts accounts for the deficits seen in TLR4 mis-sense rats. Toll-like receptor 4 (TLR4) and the transient receptor potential vanilloid subtype 1 (TRPV1) are both upregulated and play key roles in the induction and expression of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Using Apolipoprotein A-I binding protein, non-specific cholesterol depletion, TLR4 mis-sense rats and a TLR4 inhibitor, we demonstrate that co-localization of TRPV1 with TLR4 to cholesterol-rich lipid membrane rafts in nociceptors is essential for its normal activation as well as for its exaggerated activation that underlies the development and expression of CIPN. The findings suggest that TLR4-lipid rafts may have an essential role in numerous neuroinflammatory and neuropathic pain conditions. This mechanism is also generalized to female rats for the first time.
ISSN:0889-1591
1090-2139
1090-2139
DOI:10.1016/j.bbi.2024.10.017