Porphyromonas gingivalis lipopolysaccharide rapidly activates trigeminal sensory neurons and may contribute to pulpal pain

Abstract

AimTo determine whether Porphyromonas gingivalis lipopolysaccharide (LPS) can directly activate trigeminal neurons, to identify which receptors are involved and to establish whether activation leads to secretion of the neuropeptide calcitonin gene‐related peptide (CGRP) and/or the translocation of NF‐κB.MethodologyMouse trigeminal ganglion (TG) cells were cultured in vitro for 2 days. The effect of P. gingivalis LPS (20 μg mL−1) on calcium signalling was assessed (by calcium imaging using Cal‐520 AM) in comparison with the transient receptor potential channel A1 (TRPA1) agonist cinnamaldehyde (CA; 100 μmol L−1), the TRP channel V1 (TRPV1) agonist capsaicin (CAP; 1 μmol L−1) and high potassium (60 mmol L−1 KCl). TG cultures were pre‐treated with either 1 μmol L−1 CLI‐095 to block Toll‐like receptor 4 (TLR4) signalling or with 3 μmol L−1 HC‐030031 to block TRPA1 signalling. CGRP release was determined using ELISA, and nuclear translocation of NF‐κB was investigated using immunocytochemistry. Data were analysed by one‐way analysis of variance, followed by Bonferroni’s post hoc test as appropriate.ResultsPorphyromonas gingivalis LPS directly exerted a rapid excitatory response on sensory neurons and non‐neuronal cells (P < 0.001 to P < 0.05). The effects on neurons appear to be mediated via TLR4‐ and TRPA1‐dependent pathways. The responses were accompanied by an increased release of CGRP (P < 0.001) and by NF‐κB nuclear translocation (P < 0.01).ConclusionsPorphyromonas gingivalis LPS directly activated trigeminal sensory neurons (via TLR4 and TRPA1 receptors) and non‐neuronal cells, resulting in CGRP release and NF‐κB nuclear translocation. This indicates that P. gingivalis can directly influence activity in trigeminal sensory neurons and this may contribute to acute and chronic inflammatory pain.

Mechanisms of Aminoglycoside- and Cisplatin-Induced Ototoxicity

“…Activation of TRPA1 by reactive oxygen species enhanced the cellular uptake of fluorescently tagged gentamicin ( Stepanyan et al, 2011 ). This suggests that endogenous signals (e.g., pro-inflammatory cytokines and reactive oxygen species) during inflammation or noise can activate aminoglycoside-permeant TRP channels cochlear stress (e.g., noise and infection) to increase hair cell uptake of aminoglycosides ( Goncalves et al, 2020 ; Kaewpitak et al, 2020 ).…”

Oral-Gut-Brain Axis in Experimental Models of Periodontitis: Associating Gut Dysbiosis With Neurodegenerative Diseases

“…Even though the entrance origin cannot be determined from these studies, the results suggest that most Treponema spp can invade the central and peripheral nervous systems ( Riviere et al, 2002 ). Recently, the LPS of both E. coli and P. gingivalis were shown to activate TLR4 and a type of transient receptor potential (TRP) in trigeminal nerve endings and supporting non-neuronal cells ( Figure 4B ) ( Diogenes et al, 2011 ; Meseguer et al, 2014 ; Kaewpitak et al, 2020 ). The TRPs are channels located in the nociceptors, including TRPA1 and TRPV1, activated in response to bacterial infection ( Chung et al, 2011 ; Gibbs et al, 2011 ; Huang et al, 2012 ).…”

“…TRPV1 is expressed in 20–35% of trigeminal neurons, and TRPA1 is expressed in the trigeminal ganglion in approximately 6–10% of neurons ( Gibbs et al, 2011 ; Huang et al, 2012 ). The LPS of P. gingivalis activates the trigeminal neurons through the TRPA1 and TLR4-dependent pathways ( Diogenes et al, 2011 ; Meseguer et al, 2014 ; Kaewpitak et al, 2020 ). When TLR4 is activated in neurons, intracellular Ca 2+ levels increase and activate TRPA1, creating a positive enhancement of Ca 2+ signaling ( Zurborg et al, 2007 ).…”

“…Both TRPA1 and TLR4 mediate cytokine production by NF-κB, and this factor is believed to be related to the over-expression of voltage-gated Ca 2+ and Na + channels, and possibly induce allodynia, thermal hyperplasia, or chronic pain ( Huang et al, 2006 ). Besides, the neuron support cells were also activated by the effect of P. gingivalis LPS through changes in Ca 2+ and NF-κB ( Kaewpitak et al, 2020 ). Also, it was demonstrated that trigeminal nerves recognize the virulence factors of oral bacteria by the TLR4/CD14-MyD88-NF-κB axis ( Figure 4B ) ( Wadachi and Hargreaves, 2005 ).…”

Bibliometric analysis of recent research on the association between TRPV1 and inflammation

“…More and more researchers have focused on the association between TRPV1 channel and inflammation. Many reports have revealed that TRPV1 could trigger inflammatory response by releasing inflammatory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) in neuronal cells [ 16 ]. SP and CGRP exerted their pro-inflammatory role by interacting their receptors in many types of cells including T lymphocytes, macrophages, mast cells [ 17–19 ], thus arousing immune responses.…”