Sidt2 ameliorates TNF-α-induced apoptosis and inflammation by promoting autophagic flux via p65 signaling

Apical periodontitis (AP) is globally prevalent and characterized by inflammatory infiltration and periapical bone loss. The systemic RNA interference deficient-1 transmembrane family member 2 (Sidt2) is a nucleic acid transporter that plays essential roles in Apoptosis and inflammatory response. However, the effect of Sidt2 on AP remains unknown. In this study, we established an AP mouse model and treated MC3T3-E1 cells and OCCM-30 cells with tumor necrosis factor-alpha (TNF-α). Compared to the control groups, the results of Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed that Sidt2 expression was downregulated in the AP mouse model and TNF-α-treated cells, in parallel with increased Apoptosis and the production of inflammatory molecules, as evaluated by hematoxylin and eosin staining and immunohistochemistry staining. Furthermore, knockdown of Sidt2 reduced autophagic flux, aggravated TNF-α-induced Apoptosis and inflammation in vitro, as detected by flow cytometry, Western blot, enzyme-linked immunosorbent assay, and qRT-PCR, and overexpression of Sidt2 yielded the opposite results. In addition, the Autophagy inhibitors Chloroquine or 3-Methyladenine could reverse TNF-α-induced effects after overexpression of Sidt2. Moreover, knockdown of Sidt2 activated the TNF-α-induced p65 signaling, while blocking it with Pyrrolidinedithiocarbamate ammonium suppressed TNF-α-induced effects and Autophagy. Taken together, our results suggest that Sidt2 ameliorates TNF-α-induced Apoptosis and inflammation by enhancing autophagic flux via the downregulation of p65 signaling. These results demonstrate that Sidt2 functions as a negative regulator in the Apoptosis and inflammatory response of AP, and it may contribute to the development of novel diagnostic and therapeutic approaches for the disease.

Autophagy; Cell death; Dental cementum; Lysosomal membrane protein; Periapical periodontitis; Signal transduction.