Activation of mitophagy in inflamed odontoblasts

Yang, Fuhua; Li, Yuan; Duan, Huiling; Wang, Haisheng; Pei, Fei; Chen, Zhi; Zhang, Lu

doi:10.1111/odi.13110

Cited by 14 publications

(24 citation statements)

References 32 publications

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“…In our previous study, we found that autophagy was activated to regulate odontoblast differentiation [31] and that Parkin-dependent mitophagy was activated to degrade impaired mitochondria in LPS-induced odontoblasts [21]. Several studies have shown that the accumulation of abnormal mitochondria and cytoplasmic transport of mtDNA are activated by the consumption of autophagic proteins, which depend on the NALP3 inflammasome and mtROS [32].…”

Section: Discussionmentioning

confidence: 98%

“…The carious teeth group consisted of teeth collected from patients diagnosed with caries and carious lesions but without any history of spontaneous pain. The pulpitis group consisted of teeth collected from patients diagnosed with irreversible pulpitis with spontaneous pain, heat-or cold-stimulating pain and pain at night [21,22].…”

Section: Human Dental Pulp Samplesmentioning

confidence: 99%

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Mitochondrial DNA leakage induces odontoblast inflammation via the cGAS-STING pathway

et al. 2021

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Background Mitochondrial DNA (mtDNA) is a vital driver of inflammation when it leaks from damaged mitochondria into the cytosol. mtDNA stress may contribute to cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway activation in infectious diseases. Odontoblasts are the first cells challenged by cariogenic bacteria and involved in maintenance of the pulp immune and inflammatory responses to dentine-invading pathogens. In this study, we investigated that mtDNA as an important inflammatory driver participated in defending against bacterial invasion via cGAS-STING pathway in odontoblasts. Methods The normal tissues, caries tissues and pulpitis tissues were measured by western blotting and immunohistochemical staining. Pulpitis model was built in vitro to evaluated the effect of the cGAS-STING pathway in odontoblast-like cell line (mDPC6T) under inflammation. Western blot and real-time PCR were performed to detect the expression of cGAS-STING pathway and pro-inflammatory cytokines. The mitochondrial function was evaluated reactive oxygen species (ROS) generated by mitochondria using MitoSOX Red dye staining. Cytosolic DNA was assessed by immunofluorescent staining and real-time PCR in mDPC6T cells after LPS stimulation. Furthermore, mDPC6T cells were treated with ethidium bromide (EtBr) to deplete mtDNA or transfected with isolated mtDNA. The expression of cGAS-STING pathway and pro-inflammatory cytokines were measured. Results The high expression of cGAS and STING in caries and pulpitis tissues in patients, which was associated with inflammatory progression. The cGAS-STING pathway was activated in inflamed mDPC6T. STING knockdown inhibited the nuclear import of p65 and IRF3 and restricted the secretion of the inflammatory cytokines CXCL10 and IL-6 induced by LPS. LPS caused mitochondrial damage in mDPC6T, which promoted mtDNA leakage into the cytosol. Depletion of mtDNA inhibited the cGAS-STING pathway and nuclear translocation of p65 and IRF3. Moreover, repletion of mtDNA rescued the inflammatory response, which was inhibited by STING knockdown. Conclusion Our study systematically identified a novel mechanism of LPS-induced odontoblast inflammation, which involved mtDNA leakage from damaged mitochondria into the cytosol stimulating the cGAS-STING pathway and the inflammatory cytokines IL-6 and CXCL10 secretion. The mtDNA-cGAS-STING axis could be a potent therapeutic target to prevent severe bacterial inflammation in pulpitis. Graphic abstract

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Section: Discussionmentioning

confidence: 98%

Section: Human Dental Pulp Samplesmentioning

confidence: 99%

Mitochondrial DNA leakage induces odontoblast inflammation via the cGAS-STING pathway

et al. 2021

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“…2018, Yang et al . 2019), and the release of cytokines (Chung et al . 2019) via the induction of the NF‐κB pathway (Wang et al .…”

Section: Discussionmentioning

confidence: 99%

“…2003), whereas, in pathological incidents, the dynamic is shifted towards mitochondrial fission (Yang et al . 2019); whether uncontrolled, this excessive fission leads to cellular apoptosis. Aside from proteins controlling the mitochondria, Bcl‐2 and Bax, anti‐apoptotic and pro‐apoptotic proteins, respectively, are important proteins that regulate cell apoptosis by modifying the mitochondrial membrane (Salakou et al .…”

Section: Introductionmentioning

confidence: 99%

Alterations of mitochondrial dynamics, inflammation and mineralization potential of lipopolysaccharide‐induced human dental pulp cells after exposure to N‐acetyl cysteine, Biodentine or ProRoot MTA

et al. 2021

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Aim To investigate the effects of N‐acetyl cysteine (NAC), Biodentine, ProRoot MTA and their combinations, on cell viability, mitochondrial reactive oxygen species (mtROS) production, mineralization and on the expression of genes related to inflammatory cytokine production, mitochondrial dynamics and cell apoptosis of lipopolysaccharide (LPS)‐induced human dental pulp cells (hDPCs). Methodology Isolated hDPCs were exposed to 20 μg mL−1 of Escherichia coli (E. coli) LPS for 24 h, before the experiment, except for the control group. Eight experimental groups were assigned: (i) control (hDPCs cultured in regular medium), (ii) +LPS (hDPCs cultured in LPS medium throughout the experiment), (iii) −LPS/Media, (iv) −LPS/BD, (v) −LPS/MTA, (vi) −LPS/NAC, (vii) −LPS/BD + NAC and (viii) −LPS/MTA + NAC. Cell viability was measured using Alamar blue assay at 24 and 48 h. Production of mtROS was evaluated at 6 and 24 h by MitoSOX Red and MitoTracker Green. The expressions of IL‐6, TNF‐α, Bcl‐2, Bax, Mfn‐2 and Drp‐1 genes were investigated at 6 h using reverse transcriptase‐polymerase chain reaction (RT‐PCR). For differentiation potential, cells were cultured in the osteogenic differentiation media and stained using Alizarin red assay at 14 and 21 days. The Kruskal–Wallis test, Mann–Whitney U test and one‐way anova were performed for statistical analysis. Results NAC was associated with significantly greater LPS‐induced hDPC viability (P < 0.05). Both Biodentine and MTA extracts promoted cell survival, whereas the combination of NAC to these material extracts significantly increased the number of viable cells at 24 h (P < 0.05). Biodentine, MTA or NAC did not alter the mtROS level (P > 0.05). NAC supplementation to the MTA extract significantly reduced the level of IL‐6 and TNF‐α expression (P < 0.05). Regarding mitochondrial dynamics, the use of NAC alone promoted significant Mfn‐2/Drp‐1 expression (P < 0.05). Most of the groups exhibited a level of Bcl‐2/Bax gene expression similar to that of the control group. The increases in mineralization productions were observed in most of the groups, except the LPS group (P < 0.05). Conclusions The antioxidant effect of NAC was not evident under the LPS‐induced condition in DPC in vitro. NAC combined either with Biodentine or MTA improved LPS‐induced hDPCs survival at 24 h. The combination of NAC with MTA promoted mineralization.

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“…Emerging evidence implicate that autophagy involves in the pathology of pulpitis (Table 2). Autophagy and mitophagy are significantly upregulated in caries and inflammatory dental pulp samples 72,73 . In irreversible pulpitis rat model, autophagy occurs in a manner that is consistent with the progression of pulpitis 74 .…”

Section: Pathological Roles Of Autophagy In Toothmentioning

confidence: 91%

Autophagy in tooth: Physiology, disease and therapeutic implication

Yang

Fan²,

et al. 2021

Cell Biochemistry & Function

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Autophagy is an evolutionarily conserved cellular process, in which damaged organelles and proteins are engulfed in autophagic vesicles and subsequently fuse with lysosomes for degradation. Autophagy is widely involved in different physiologic or pathologic processes in human. Accumulating evidence indicates that autophagy operates as a critical quality control mechanism to maintain pulp homeostasis and structural integrity of the dentin‐pulp complex. Autophagy is activated during stresses and is involved in the pathogenesis of pulpitis and periapical infection. Recent discoveries have also provided intriguing insights into the roles of autophagy in tooth development, pulp aging and stress adaptation. In this review, we provide an update on the multifaceted functions of autophagy in physiology and pathophysiology of tooth. We also discuss the therapeutic implications of autophagy modulation in diseases and the regeneration of dentin‐pulp complex.

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Activation of mitophagy in inflamed odontoblasts

Cited by 14 publications

References 32 publications

Mitochondrial DNA leakage induces odontoblast inflammation via the cGAS-STING pathway

Mitochondrial DNA leakage induces odontoblast inflammation via the cGAS-STING pathway

Alterations of mitochondrial dynamics, inflammation and mineralization potential of lipopolysaccharide‐induced human dental pulp cells after exposure to N‐acetyl cysteine, Biodentine or ProRoot MTA

Autophagy in tooth: Physiology, disease and therapeutic implication

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