bay-11-7082 and Periodontitis

Periodontitis is a chronic osteolytic inflammatory disease resulting from complex dynamic interactions among bacterial pathogens and the host immune response. Macrophages play a vital role in the pathogenesis of periodontitis by triggering periodontal inflammation and inducing periodontium destruction. N-Acetyltransferase 10 (NAT10) is an acetyltransferase that has been shown to catalyse N4-acetylcytidine (ac4C) mRNA modification and is related to cellular pathophysiological processes, including the inflammatory immune response. Nevertheless, whether NAT10 regulates the inflammatory response of macrophages in periodontitis remains unclear. In this study, the expression of NAT10 in macrophages was found to decrease during LPS-induced inflammation. NAT10 knockdown significantly reduced the generation of inflammatory factors, while NAT10 overexpression had the opposite effect. RNA sequencing revealed that the differentially expressed genes were enriched in the NF-κB signalling pathway and oxidative stress. Both the NF-κB inhibitor Bay11-7082 and the ROS scavenger N-acetyl-L-cysteine (NAC) could reverse the upregulation of inflammatory factors. NAC inhibited the phosphorylation of NF-κB, but Bay11-7082 had no effect on the production of ROS in NAT10-overexpressing cells, suggesting that NAT10 activated the LPS-induced NF-κB signalling pathway by regulating ROS generation. Furthermore, the expression and stability of Nox2 was promoted after NAT10 overexpression, indicating that Nox2 may be a potential target of NAT10. In vivo, the NAT10 inhibitor Remodelin reduced macrophage infiltration and bone resorption in ligature-induced periodontitis mice. In summary, these results showed that NAT10 accelerated LPS-induced inflammation via the NOX2-ROS-NF-κB pathway in macrophages and that its inhibitor Remodelin might be of potential therapeutic significance in periodontitis treatment.

Topics: Animals; Inflammation; Lipopolysaccharides; Macrophages; Mice; NADPH Oxidase 2; NF-kappa B; Periodontitis; Reactive Oxygen Species

Periapical lesions are characterized by the destruction of periapical bone, and occur as a result of local inflammatory responses to root canal infection by microorganisms including Porphyromonas endodontalis (P. endodontalis). P. endodontalis and its primary virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical lesions and alveolar bone loss. Interleukin‑23 (IL‑23) is critical in the initiation and progression of periodontal disease via effects on peripheral bone metabolism. The present study investigated the expression of IL‑23 in tissue where a periapical lesion was present, and the effect of P. endodontalis LPS on the expression of IL‑23 in periodontal ligament (PDL) cells. Reverse transcription‑ quantitative polymerase chain reaction and immunohistochemistry revealed increased levels of IL‑23 expression in tissue with periapical lesions compared with healthy PDL tissue. Treatment with P. endodontalis LPS increased the expression of IL‑23 in the SH‑9 human PDL cell line. BAY11‑7082, a nuclear factor κB inhibitor, suppressed P. endodontalis LPS‑induced IL‑23 expression in SH‑9 cells. Treatment of RAW264.7 cells with conditioned medium from P. endodontalis LPS‑treated SH‑9 cells promoted osteoclastogenesis. By contrast, RAW264.7 cells treated with conditioned medium from IL‑23‑knockdown SH‑9 cells underwent reduced levels of osteoclastogenesis. The results of the present study indicated that the expression of IL‑23 in PDL cells induced by P. endodontalis LPS treatment may be involved in the progression of periapical lesions via stimulation of the osteoclastogenesis process.

Topics: Animals; Chromones; Humans; Immunohistochemistry; Interleukin-23; Lipopolysaccharides; Mice; Morpholines; NF-kappa B; NFATC Transcription Factors; Nitriles; Osteoblasts; Osteogenesis; Periodontitis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Porphyromonas endodontalis; Proto-Oncogene Proteins c-fos; RANK Ligand; RAW 264.7 Cells; RNA Interference; RNA, Small Interfering; Sulfones