Sensory Neuron TLR4 mediates the development of nerve-injury induced mechanical hypersensitivity in female mice

Szabo-Pardi, Thomas A.; Barron, Luz R.; Lenert, Melissa E.; Burton, Michael D.

doi:10.1016/j.bbi.2021.06.011

Cited by 44 publications

(28 citation statements)

References 72 publications

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“…The authors also showed that this sex-dimorphic response to TLR4 was dependent on macrophages and microglia; removal of TLR4 from sensory neurons did not result in hypersensitivity in male or female mice ( Rudjito et al, 2021 ). Other findings by the same group also supported this finding: TLR4 in the sensory neurons is required for female mechanical hypersensitivity upon nerve injury ( Szabo-Pardi et al, 2021 ). Hence, TLR4 seems to be important for pain in both sexes (in the sensory neuron), but is sexually dimorphic in the macrophages and microglia.…”

Section: Sex Differences In the Pain Compartmentsupporting

confidence: 54%

“…Additionally, TLR4 is present in a soluble form in the synovial fluid of OA patients, and was associated with OA severity, suggesting TLR4 as a potential OA biomarker ( Barreto et al, 2017 ). The findings of preclinical studies have suggested that differences in innate immunity, associated with TLR4 activation, may contribute to sex differences in pain ( Sorge et al, 2011 ; Sorge et al, 2015 ; Szabo-Pardi et al, 2021 ). In the next section, we describe how inflammatory mediators contribute to OA pain, highlighting recent findings showing differences between sexes.…”

Section: Innate-immunity-related Oa Painmentioning

confidence: 99%

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Innate Immunity at the Core of Sex Differences in Osteoarthritic Pain?

et al. 2022

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Osteoarthritis (OA) is a progressive whole-joint disease; no disease-modifying drugs are currently available to stop or slow its process. Symptoms alleviation is the only treatment option. OA is the major cause of chronic pain in adults, with pain being the main symptom driving patients to seek medical help. OA pathophysiology is closely associated with the innate immune system, which is also closely linked to pain mediators leading to joint pain. Pain research has shown sex differences in the biology of pain, including sexually dimorphic responses from key cell types in the innate immune system. Not only is OA more prevalent in women than in men, but women patients also show worse OA outcomes, partially due to experiencing more pain symptoms despite having similar levels of structural damage. The cause of sex differences in OA and OA pain is poorly understood. This review provides an overview of the involvement of innate immunity in OA pain in joints and in the dorsal root ganglion. We summarize the emerging evidence of sex differences regarding innate immunity in OA pain. Our main goal with this review was to provide a scientific foundation for future research leading to alternative pain relief therapies targeting innate immunity that consider sex differences. This will ultimately lead to a more effective treatment of pain in both women and men.

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Section: Sex Differences In the Pain Compartmentsupporting

confidence: 54%

Section: Innate-immunity-related Oa Painmentioning

confidence: 99%

Innate Immunity at the Core of Sex Differences in Osteoarthritic Pain?

et al. 2022

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“…Numerous studies have investigated GABAα2-mediated analgesia in neuropathic pain, given that the absence of GABAα2 is a classic neuropathic pain sign accompanied by neuroinflammation [ 16 , 17 ]. Spared nerve injury (SNI) is the most recognized method for simulating neuropathic pain [ 18 , 19 ]. Numerous studies on the pathogenesis, prevention, and treatment of neuropathic pain have suggested that the pain threshold is sex-specific [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Positive interaction between GPER and β-alanine in the dorsal root ganglion uncovers potential mechanisms: mediating continuous neuronal sensitization and neuroinflammation responses in neuropathic pain

Xie

Feng

et al. 2022

J Neuroinflammation

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Background The pathogenesis of neuropathic pain and the reasons for the prolonged unhealing remain unknown. Increasing evidence suggests that sex oestrogen differences play a role in pain sensitivity, but few studies have focused on the oestrogen receptor which may be an important molecular component contributing to peripheral pain transduction. We aimed to investigate the impact of oestrogen receptors on the nociceptive neuronal response in the dorsal root ganglion (DRG) and spinal dorsal horn using a spared nerve injury (SNI) rat model of chronic pain. Methods We intrathecally (i.t.) administered a class of oestrogen receptor antagonists and agonists intrathecal (i.t.) administrated to male rats with SNI or normal rats to identify the main receptor. Moreover, we assessed genes identified through genomic metabolic analysis to determine the key metabolism point and elucidate potential mechanisms mediating continuous neuronal sensitization and neuroinflammatory responses in neuropathic pain. The excitability of DRG neurons was detected using the patch-clamp technique. Primary culture was used to extract microglia and DRG neurons, and siRNA transfection was used to silence receptor protein expression. Immunofluorescence, Western blotting, RT-PCR and behavioural testing were used to assess the expression, cellular distribution, and actions of the main receptor and its related signalling molecules. Results Increasing the expression and function of G protein-coupled oestrogen receptor (GPER), but not oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ), in the DRG neuron and microglia, but not the dorsal spinal cord, contributed to SNI-induced neuronal sensitization. Inhibiting GPER expression in the DRG alleviated SNI-induced pain behaviours and neuroinflammation by simultaneously downregulating iNOS, IL-1β and IL-6 expression and restoring GABAα2 expression. Additionally, the positive interaction between GPER and β-alanine and subsequent β-alanine accumulation enhances pain sensation and promotes chronic pain development. Conclusion GPER activation in the DRG induces a positive association between β-alanine with iNOS, IL-1β and IL-6 expression and represses GABAα2 involved in post-SNI neuropathic pain development. Blocking GPER and eliminating β-alanine in the DRG neurons and microglia may prevent neuropathic pain development.

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“…Indeed, our transcriptional analyses confirm the expression of both RAGE and TLR4 in subsets of vagal sensory neurons displaying a nociceptor phenotype (i.e., neurons expressing TRPV1 or the neuropeptide CGRP), while our functional studies show that HMGB1 both excites and enhances the growth of vagal ganglia sensory neurons, responses that were largely abrogated in neurons lacking RAGE expression. However, a very recent study suggests TLR4 expression in DRG neurons may be important in nerve injury-mediated hypersensitivity specifically in female mice (Szabo-Pardi et al, 2021), something that our study did not address.…”

Section: Discussionmentioning

confidence: 60%

Modulation of Vagal Sensory Neurons via High Mobility Group Box-1 and Receptor for Advanced Glycation End Products: Implications for Respiratory Viral Infections

et al. 2021

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Vagal sensory neurons contribute to the symptoms and pathogenesis of inflammatory pulmonary diseases through processes that involve changes to their morphological and functional characteristics. The alarmin high mobility group box-1 (HMGB1) is an early mediator of pulmonary inflammation and can have actions on neurons in a range of inflammatory settings. We hypothesized that HMGB1 can regulate the growth and function of vagal sensory neurons and we set out to investigate this and the mechanisms involved. Culturing primary vagal sensory neurons from wildtype mice in the presence of HMGB1 significantly increased neurite outgrowth, while acute application of HMGB1 to isolated neurons under patch clamp electrophysiological investigation produced inward currents and enhanced action potential firing. Transcriptional analyses revealed the expression of the cognate HMGB1 receptors, Receptor for Advanced Glycation End products (RAGE) and Toll-like Receptor 4 (TLR4), in subsets of vagal sensory neurons. HMGB1-evoked growth and electrophysiological responses were significantly reduced in primary vagal sensory neurons harvested from RAGE deficient mice and completely absent in neurons from RAGE/TLR4 double deficient mice. Immunohistochemical analysis of vagal sensory neurons collected from mice after intranasal infection with murine pneumovirus or influenza A virus (IAV), or after intratracheal administration with the viral mimetic PolyI:C, revealed a significant increase in nuclear-to-cytoplasm translocation of HMGB1 compared to mock-inoculated mice. Neurons cultured from virus infected wildtype mice displayed a significant increase in neurite outgrowth, which was not observed for neurons from virus infected RAGE or RAGE/TLR4 deficient mice. These data suggest that HMGB1 can enhance vagal sensory neuron growth and excitability, acting primarily via sensory neuron RAGE. Activation of the HMGB1-RAGE axis in vagal sensory neurons could be an important mechanism leading to vagal hyperinnervation and hypersensitivity in chronic pulmonary disease.

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Sensory Neuron TLR4 mediates the development of nerve-injury induced mechanical hypersensitivity in female mice

Cited by 44 publications

References 72 publications

Innate Immunity at the Core of Sex Differences in Osteoarthritic Pain?

Innate Immunity at the Core of Sex Differences in Osteoarthritic Pain?

Positive interaction between GPER and β-alanine in the dorsal root ganglion uncovers potential mechanisms: mediating continuous neuronal sensitization and neuroinflammation responses in neuropathic pain

Modulation of Vagal Sensory Neurons via High Mobility Group Box-1 and Receptor for Advanced Glycation End Products: Implications for Respiratory Viral Infections

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