Mitochondrial DNA leakage exacerbates odontoblast inflammation through gasdermin D-mediated pyroptosis

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.

Gasdermin D-mediated pyroptosis in myocardial ischemia and reperfusion injury: Cumulative evidence for future cardioprotective strategies

“…Recently, mtDNA, that is liberated from damaged mitochondria to the cytosol or extracellular space, is recognized as important DAMPs to trigger various inflammatory or degenerative diseases 31 . Mechanically, mtDNA DAMP activates TLR9/NLRP3/GSDMD pathways 32 , then, IL-1 β and IL-18 are released from the injured cells 32 . Despite this pathway, activation of TLR could induce innate and adaptive immune systems in cardiac cells.…”

Innate immune sensing of nucleic acid in endodontic infection

“…Activated gasdermin D feedback inhibits the STING signalling pathway. Therefore, cGAS‐STING pathway and GSDMD‐mediated pyroptosis are mutually compensatory mechanisms, cooperatively contributing to the immune inflammation in odontoblasts (Zhang et al, 2021; Zhou et al, 2021). In summary, mtDNA, as an important inflammatory driver, could participate in the progression of odontoblast inflammation and affect the dentine‐pulp complex that defends against microbial invasion.…”

Dexpramipexole ameliorates cognitive deficits in sepsis-associated encephalopathy through suppressing mitochondria-mediated pyroptosis and apoptosis

“…In the mitochondria, apoptosis-associated proteins, such as BCL-2-associated X (BAX), promote mitochondrial permeability transition, thus causing the release of cytochrome c (Cyt-c) and cleavage of caspase-3, and subsequently a series of caspase cascades leading to cell death [12,14]. Pyroptosis, a recently characterized inflammatory form of programmed cell death, can be divided into three types according to different activation modes: the canonical Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1 pathway, non-canonical caspase-4/5/11 pathway and apoptosis protein caspase-3 mediated pyroptosis pathway [15][16][17]. Gasdermin D (GSDMD) is a key executioner in the progression of pyroptosis.…”