Robust expression of SIRT6 inhibits pulpitis via activation of the TRPV1 channel

Abstract

Invasion of dentinal tubules and pulp tissue by pathogenic bacteria may cause infection leading to pulpitis. Sirtuin 6 (SIRT6) is a NAD‐dependent protein deacetylase encoded by the SIRT6 gene. The effect of SIRT6 on lipopolysaccharide (LPS)‐induced pulpitis and its mechanism of action were discussed in this study. Dental pulp cells (DPCs) were extracted from human teeth and injected with LPS to induce inflammation. The cells injected with LPS showed substantially decreased expression of SIRT6. The overexpression of SIRT6, induced by plasmid‐transfection of DPCs with SIRT6 overexpressing vector, led to a marked decrease in proinflammatory cytokines (IL‐6, IL‐1β, and TNF‐α) and deactivation of NF kappa B pathway. Additionally, dentin matrix protein‐1 (DMP1), a promoter of inflammation in dental pulp tissues, was downregulated. Further investigation revealed that SIRT6 promotes ubiquitination of the transient receptor potential vanilloid 1 (TRPV1) channel, leading to its degradation and deactivation. The role of TRPV1 in the anti‐inflammatory effects of SIRT6 was determined through incubation of SIRT6‐expressing dental pulp stem cells (DPSCs) with capsaicin. This incubation counteracted the effect of SIRT6 on cytokines and DMP1. The injection of lentivirus‐SIRT6 attenuated LPS‐induced pulpitis in vivo by suppressing TRPV1 activity. Thus, SIRT6 inhibits the TRPV1 channel during LPS‐induced inflammation of dental pulp.Significance of the StudyThis study discussed the effect of sirtuin 6 (SIRT6) on lipopolysaccharide (LPS)‐induced pulpitis as well as its mechanism of action and found that SIRT6 may be a negative regulator of pulpitis. Additionally, low expression of SIRT6 and high expression of transient receptor potential vanilloid 1 (TRPV1) in LPS‐treated human dental pulp cells are closely associated with proinflammatory cytokines, dentin matrix protein 1 expression, and activation of the NF‐κB pathway, which indicated that TRPV1 may be a biomarker for pulpitis and the SIRT6‐TRPV1‐CGRP axis maybe a clinical target due to their role regulating inflammation and neuropathic pain.

Role of Lipopolysaccharide, Derived from Various Bacterial Species, in Pulpitis—A Systematic Review

“…Another way LPS works is by activating transient receptor potential vanilloid 1 (TRPV1) canal. Overexpression of SIRT6 protein, which promotes degradation of TRPV1 via its ubiquitination, reduces expression of cytokines—IL-6, IL-1β, and TNF-α, deactivates NF-κB and lowers DMP1 level [ 107 ]. Capsaicin stimulates TRPV1 in SIRT6-overexpressed cells, counteracting anti-inflammatory properties [ 107 ].…”

Total Sesquiterpene Glycosides from Loquat Leaves Ameliorate HFD‐Induced Insulin Resistance by Modulating IRS‐1/GLUT4, TRPV1, and SIRT6/Nrf2 Signaling Pathways

“…Furthermore, it is worth noting that SIRT6 has been suggested to take a part in TRPV1-mediated inflammation. In the inflammatory state, the level of SIRT6 was decreased while TRPV1 expression was upregulated [ 30 , 77 ]. Overexpression of SIRT6 could suppress TRPV1 and result in significant downregulation ROS and NF- κ B production, achieving anti-inflammatory effect [ 31 ].…”

“…SIRT6 has been well established to promote nuclear factor erythroid 2-related factor 2 (Nrf2) binding the antioxidant response elements (AREs) and to protect cells from oxidative stress [ 29 ]. Additionally, robust expression of SIRT6 has been shown an inhibitory effect on TRPV1-regulated inflammation [ 30 , 31 ]. Thus, promoting the SIRT6/Nrf2 signaling will be a distinctive strategy to curb IR.…”

SIRT1: A promising therapeutic target for chronic pain

“…[139][140][141] In lipopolysaccharideinduced pulpitis, Hu et al demonstrated that overexpression of SIRT6 led to a significant reduction in proinflammatory cytokines (IL-6, IL-1 β, and TNFα) and inactivation of the NF-κB pathway, thereby attenuating pain caused by pulpitis. 142 Therefore, the above evidence indicates that other sirtuins may act as potential targets for the prevention and treatment of chronic pain. Large-scale, multicenter, prospective clinical trials are needed.…”

“…It has been reported that SIRT3 improves the ability of mitochondria to reduce ROS levels and protect against oxidative stress by regulating the activity of key antioxidant enzymes, such as manganese superoxide dismutase 139‐141 . In lipopolysaccharide‐induced pulpitis, Hu et al demonstrated that overexpression of SIRT6 led to a significant reduction in proinflammatory cytokines (IL‐6, IL‐1 β, and TNF‐α) and inactivation of the NF‐κB pathway, thereby attenuating pain caused by pulpitis 142 . Therefore, the above evidence indicates that other sirtuins may act as potential targets for the prevention and treatment of chronic pain.…”