AIBP regulates TRPV1 activation in chemotherapy-induced peripheral neuropathy by controlling lipid raft dynamics and proximity to TLR4 in dorsal root ganglion neurons

Navia-Pelaez, Juliana Maria; Lemes, Júlia Borges Paes; González, Leonardo Tovar; Delay, Lauriane; Capettini, Luciano dos Santos Aggum; Lu, Jenny W; Santos, Gilson Gonçalves dos; Gregus, Ann M.; Dougherty, Patrick M.; Yaksh, Tony L.; Miller, Yury I.

doi:10.1097/j.pain.0000000000002834

Cited by 21 publications

(12 citation statements)

References 43 publications

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“…Paclitaxel (Taxol), a widely used chemotherapeutic agent, is known to induce both acute and chronic CIPN. Considering the role of OMDs in regulating voltage-gated ion channels and the previously reported role of paclitaxel in regulating membrane lipid domains 14,30,55,56 , we postulated that the paclitaxel-triggered neuropathy might be associated with alterations in the lipid domain organization of nociceptor DRG neurons. Using FLIM-FRET and the same CTxB-mediated labeling approach, our results revealed that overnight treatment using either a low concentration (10 nM) or a saturating concentration (1 μM) of paclitaxel resulted in a significant reduction in the FLIM-FRET efficiency of small DRG neurons (Fig.…”

Section: Resultsmentioning

confidence: 91%

“…Inflammatory responses involve the reorganization of lipid domains, influencing cell signaling and immune responses. Moreover, emerging evidence suggests a link between lipid domains and chronic pain, particularly neuropathic pain that is often caused by nerve injuries (12, 13). In an animal model of chemotherapy-induced peripheral neuropathy and arthritis, targeting of lipid domains was effective to alleviate the pathological symptoms (14).…”

Section: Introductionmentioning

confidence: 99%

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Membrane Lipid Nanodomains Modulate HCN Pacemaker Channels in Nociceptor DRG Neurons

Handlin,

Macchi,

Dumaire

et al. 2023

Preprint

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Cell membranes consist of heterogeneous lipid domains that influence key cellular processes, including signal transduction, endocytosis, and electrical excitability. The goal of this study was to assess the size of cholesterol-enriched ordered membrane domains (OMD) in various cell types. Multiple cell types were tested using fluorescence lifetime imaging microscopy (FLIM) and Förster resonance energy transfer (FRET), whereby small nociceptor DRG neurons and cardiac pacemaker cells displayed the highest FRET intensities. This implies that electrically active cells tend to have large OMDs. Treatment of cells with the cholesterol-extracting reagent β-cyclodextrin (β-CD) led to a decrease in FRET, indicating a reduction in the OMD size, whereas detergents known to promote domain coalescence in artificial membranes increased OMD size. In an in vitro fatty liver model, palmitate supplementation increased FRET whereas oleate supplementation decreased FRET in isolated primary murine hepatocytes, highlighting the importance of unsaturated lipid tails in lipid domain organization. Disruption of OMD using β-CD potentiated action potential firing in nociceptor DRG neurons and decreased the free energy needed for opening native hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. After disrupting the OMD, HCN channels exhibited an increased relative open probability at the resting membrane potential (RMP). A significant reduction in FRET was observed in both a chemotherapy-induced neuropathic pain model and a spared nerve injury model of neuropathic pain, consistent with disrupted or shrunken OMD in these models. Collectively, these findings show that disturbances in lipid domains may contribute to the progression of neuropathic pain, and they suggest new therapeutic strategies to achieve pain relief.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Membrane Lipid Nanodomains Modulate HCN Pacemaker Channels in Nociceptor DRG Neurons

Handlin,

Macchi,

Dumaire

et al. 2023

Preprint

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“…However, in the human TG, KCNA1 expression was observed in neurons (percent = 49.1%) and to a much lesser extent in SGCs (percent = 1.7%) and SCs (percent = 3.1%), compared to its expression in mouse TG ( Figure 3C ). TLR4 (Toll-Like Receptor 4), which plays a role in pathogen recognition and innate immunity, is associated with pain ( Navia-Pelaez et al, 2022 ) and has been validated for expression in SGCs of human and rat TG ( Tse et al, 2014 ; Mitterreiter et al, 2017 ). The results of this study further verified that Tlr4 was significantly expressed in the SGCs of the human TG (20%) ( Figure 3C ), but was poorly expressed in mouse SGCs (1%) ( Figure 3D ).…”

Section: Resultsmentioning

confidence: 99%

Single-nucleus transcriptome analysis reveals transcriptional profiles of circadian clock and pain related genes in human and mouse trigeminal ganglion

Chu

Jia

et al. 2023

Front. Neurosci.

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IntroductionClinical studies have revealed the existence of circadian rhythms in pain intensity and treatment response for chronic pain, including orofacial pain. The circadian clock genes in the peripheral ganglia are involved in pain information transmission by modulating the synthesis of pain mediators. However, the expression and distribution of clock genes and pain-related genes in different cell types within the trigeminal ganglion, the primary station of orofacial sensory transmission, are not yet fully understood.MethodsIn this study, data from the normal trigeminal ganglion in the Gene Expression Omnibus (GEO) database were used to identify cell types and neuron subtypes within the human and mouse trigeminal ganglion by single nucleus RNA sequencing analysis. In the subsequent analyses, the distribution of the core clock genes, pain-related genes, and melatonin and opioid-related genes was assessed in various cell clusters and neuron subtypes within the human and mouse trigeminal ganglion. Furthermore, the statistical analysis was used to compare the differences in the expression of pain-related genes in the neuron subtypes of trigeminal ganglion.ResultsThe present study provides comprehensive transcriptional profiles of core clock genes, pain-related genes, melatonin-related genes, and opioid-related genes in different cell types and neuron subtypes within the mouse and human trigeminal ganglion. A comparative analysis of the distribution and expression of the aforementioned genes was conducted between human and mouse trigeminal ganglion to investigate species differences.DiscussionOverall, the results of this study serve as a primary and valuable resource for exploring the molecular mechanisms underlying oral facial pain and pain rhythms.

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“…Apolipoprotein A-I binding protein (AIBP) is a new, selective regulator of inflammarafts. AIBP binds to TLR4 and thus facilitates cholesterol depletion primarily from cells expressing high surface levels of TLR4, such as dorsal root ganglia (DRG) nociceptive neurons and macrophages and activated spinal microglia [19 ▪▪ ,37]. Intrathecal administration of AIBP reverses established neuropathic pain in mouse models, with the therapeutic effect of a single dose lasting for over 2 months [18,19 ▪▪ ].…”

Section: Inflammarafts As a Therapeutic Targetmentioning

confidence: 99%

Macrophage inflammarafts in atherosclerosis

Li,

Navia-Pelaez,

Choi

et al. 2023

Current Opinion in Lipidology

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Purpose of review Advances in single cell techniques revealed a remarkable diversity in macrophage gene expression profiles in atherosclerosis. However, the diversity of functional processes at the macrophage plasma membrane remains less studied. This review summarizes recent advances in characterization of lipid rafts, where inflammatory receptors assemble, in macrophages that undergo reprogramming in atherosclerotic lesions and in vitro under conditions relevant to the development of atherosclerosis. Recent findings The term inflammarafts refers to enlarged lipid rafts with increased cholesterol content, hosting components of inflammatory receptor complexes assembled in close proximity, including TLR4-TLR4, TLR2-TLR1 and TLR2-CD36 dimers. Macrophages decorated with inflammarafts maintain chronic inflammatory gene expression and are primed to an augmented response to additional inflammatory stimuli. In mouse atherosclerotic lesions, inflammarafts are expressed primarily in nonfoamy macrophages and less in lipid-laden foam cells. This agrees with the reported suppression of inflammatory programs in foam cells. In contrast, nonfoamy macrophages expressing inflammarafts are the major inflammatory population in atherosclerotic lesions. Discussed are emerging reports that help understand formation and persistence of inflammarafts and the potential of inflammarafts as a novel therapeutic target. Summary Chronic maintenance of inflammarafts in nonfoamy macrophages serves as an effector mechanism of inflammatory macrophage reprogramming in atherosclerosis.

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AIBP regulates TRPV1 activation in chemotherapy-induced peripheral neuropathy by controlling lipid raft dynamics and proximity to TLR4 in dorsal root ganglion neurons

Cited by 21 publications

References 43 publications

Membrane Lipid Nanodomains Modulate HCN Pacemaker Channels in Nociceptor DRG Neurons

Membrane Lipid Nanodomains Modulate HCN Pacemaker Channels in Nociceptor DRG Neurons

Single-nucleus transcriptome analysis reveals transcriptional profiles of circadian clock and pain related genes in human and mouse trigeminal ganglion

Macrophage inflammarafts in atherosclerosis

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