Targeting TLR4-Lipid Rafts Reverses Hyperexcitability in Pain-Associated Human Dorsal Root Ganglia

Authors:
  • MUMegan L. Uhelski
    Megan L. Uhelski
  • RNRobert Y. North
    Robert Y. North
  • HEHajira Elahi
    Hajira Elahi
  • MHMario Heles
    Mario Heles
  • JNJuliana M. Navia-Pelaez
    Juliana M. Navia-Pelaez
  • CBChristopher B. Bankston
    Christopher B. Bankston
  • GCGerman Corrales
    German Corrales
  • NCNicolas A. Cortes-Mejia
    Nicolas A. Cortes-Mejia
  • JCJuan P. Cata
    Juan P. Cata
  • LFLuke B. Farson
    Luke B. Farson
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Abstract
Cholesterol-rich lipid rafts are organizing platforms for many excitatory ion channels and receptors in neurons and for inflammatory receptors like toll-like receptor 4 (TLR4) in immune cells. Human dorsal root ganglion (hDRG) neurons that express nociceptor markers also express high levels of TLR4. Apolipoprotein A-I binding protein (AIBP) binds to TLR4 and promotes cholesterol depletion and lipid raft disruption in cells where TLR4 is expressed. The current study conducted with male and female hDRG demonstrates that TLR4-lipid rafts are expressed with higher density in pain- versus non-pain-associated tissues and localized to neurons expressing transient receptor potential vanilloid 1 (TRPV1) typically expressed by nociceptors. This increased density of TLR4-lipid rafts results in increased excitability of hDRG TRPV1 receptors. Additionally, whole-cell recordings show that disruption of TLR4-rafts with AIBP inhibited pain-associated ectopic action potential generation and evoked neuronal excitation in hDRG neurons. AIBP treatment impacted several action potential dynamics specifically in cells with ongoing ectopic action potentials rather than nonspontaneously active neurons. Finally, AIBP is shown to be localized with satellite cells in human DRG and its expression increases along with glutamine synthetase in pain-associated hDRG. Given that TLR4-raft expression in DRG neurons is largely confined to nociceptors, a TLR4-raft-specific therapeutic such as AIBP may have potential as a novel pain therapeutic with a low-side effect profile.
Funding Information
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS111929)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS130608)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS132483)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS132483)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS132483)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS102432)
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS104769)

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