Abstract
Alleviating odontoblast inflammation is crucial to control the progression of pulpitis. Mitochondrial DNA (mtDNA) is a vital driver of inflammation when it leaks from mitochondria of inflamed odontoblasts into the cytosol. Bacteria-induced inflammation leads to a novel type of cell death named pyroptosis. The canonical pyroptosis is a gasdermin (GSDM)-dependent cytolytic programmed cell death characterized by cell swelling and pore formation in the plasma membrane. To date, whether odontoblast cytosolic mtDNA regulates dental pulp inflammation through the canonical pyroptosis pathway remains to be elucidated. In this study, high gasdermin D (GSDMD) expression was detected in human pulpitis. We found that LPS stimulation of mDPC6T cells promoted BAX translocation from the cytosol to the mitochondrial membrane, leading to mtDNA release. Moreover, overexpression of isolated mtDNA induced death in a large number of mDPC6T cells, which had the typical appearance of pyroptotic cells. Secretion of the inflammatory cytokines CXCL10 and IFN-β was also induced by mtDNA. These results suggest that cytosolic mtDNA participates in the regulation of odontoblast inflammation through GSDMD-mediated pyroptosis in vitro. Interestingly, after overexpression of mtDNA, the expression of inflammatory cytokines CXCL10 and IFN-β was increased and not decreased in GSDMD knockdown mDPC6T cells. We further proposed a novel model in which STING-dependent inflammation in odontoblast-like cell is a compensatory mechanism to control GSDMD-mediated pyroptosis, jointly promoting the immune inflammatory response of odontoblasts. Collectively, these findings provide the first demonstration of the role of the mtDNA-GSDMD-STING in controlling odontoblast inflammation and a detailed description of the underlying interconnected relationship.
Highlights
According to Global Burden of Diseases, Injuries, and Risk Factors Study 2016 data, global incidence of dental caries was the second [1]
This study reveals a new mechanism of cytosolic Mitochondrial DNA (mtDNA)-mediated inflammation of odontoblasts and is expected to provide new Immunofluorescence and confocal laser scanning microscopy Cells were grown on confocal dishes and treated with 20 μg/mL LPS for 24 h. mDPC6T cells were incubated with 200 mM MitoTracker (Invitrogen, USA) for 15 min and fixed with paraformaldehyde, permeabilized with 3% Triton X-100 and blocked with 10% bovine serum albumin for 1 h
From our previous [11] and present study, cytosolic mtDNA promotes pulp inflammation through the pyroptosis pathway and the STING pathway, suggesting that protecting mitochondria and reducing mtDNA leakage under inflammatory stimuli can delay the progression of inflammation
Summary
According to Global Burden of Diseases, Injuries, and Risk Factors Study 2016 data, global incidence of dental caries was the second [1]. When the hard tissue of the tooth is damaged due to caries, bacteria can enter through the defect and infect the pulp tissue, causing pulp inflammation [2]. Odontoblasts in dental pulp tissue are the first line of defense against bacteria [3]. Alleviating inflammation of odontoblasts is critical to control the progression of pulpitis. Inflammation is a part of the customary protective immune response and it promotes recruitment of immune cells to the damage site and eliminates injurious pathogens. Mitochondrial damage can cause the release of mitochondrial ROS, mitochondrial DNA, Cytochrome c and other substances [4, 5] and play an important role in the pathogenesis of pulpitis. Mitochondrial DNA (mtDNA) is the genetic material of mitochondria and primarily encodes proteins for oxidative phosphorylation, which provides energy for various life activities [6]
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