Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1–mediated immunoescape via STING-IFN signaling and extracellular vesicles

Cheng, An; Cheng, Li-Chun; Kuo, Cheng-Liang; Lo, Yu Kang; Chou, Han‐Yu; Chen, Chung–Hsing; Wang, Yihao; Chuang, Tsung‐Hsien; Cheng, Shih‐Jung; Lee, Alan Yueh‐Luen

doi:10.1136/jitc-2020-001372

Cited by 89 publications

(87 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…When mtDNA was overexpressed, inflammatory cytokines, such CXCL10 and IFN-β, were increased in GSDMD knockdown cells, suggesting that STING activates IFN-β and CXCL10 production in the absence of GSDMD via mtDNA-associated PRRs and provide a compensatory mechanism for response to inflammatory infection in odontoblast GSDMD deficiency. Previous evidence has shown that mtDNA activates the STING pathway as a cell-intrinsic cGAS ligand and that cytosolic mtDNA mainly participates in the regulation of the cellular inflammatory response by activating the STING pathway [ 31 , 32 ]. In macrophages, GSDMD can not only mediate pyroptosis but also inhibit activation of the STING pathway through K + efflux to inhibit the IFN-β response [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Endothelial microparticles (EMPs) derived from lipopolysaccharide-treated endothelial cells contain dysfunctional mitochondria, which contributed to the EMPs-mediated inflammatory response 75 . Mitochondrial Lon induced the release of EVs-containing mtDNA, which enhances the M2 macrophages function through the TLR9-dependent pathway and inhibits CD8+ T cell activity, promoting tumor progression 84 . Tsilioni et al found that EVs-containing mtDNA derived from the serum of patients with autism spectrum disorder promote the secretion of more proinflammatory factor IL-1β in human microglia 85 (Fig.…”

Section: The Transfer Of Mitochondria Between Cellsmentioning

confidence: 99%

The effect of extracellular vesicles on the regulation of mitochondria under hypoxia

et al. 2021

View full text Add to dashboard Cite

Mitochondria are indispensable organelles for maintaining cell energy metabolism, and also are necessary to retain cell biological function by transmitting information as signal organelles. Hypoxia, one of the important cellular stresses, can directly regulates mitochondrial metabolites and mitochondrial reactive oxygen species (mROS), which affects the nuclear gene expression through mitochondrial retrograde signal pathways, and also promotes the delivery of signal components into cytoplasm, causing cellular injury. In addition, mitochondria can also trigger adaptive mechanisms to maintain mitochondrial function in response to hypoxia. Extracellular vesicles (EVs), as a medium of information transmission between cells, can change the biological effects of receptor cells by the release of cargo, including nucleic acids, proteins, lipids, mitochondria, and their compositions. The secretion of EVs increases in cells under hypoxia, which indirectly changes the mitochondrial function through the uptake of contents by the receptor cells. In this review, we focus on the mitochondrial regulation indirectly through EVs under hypoxia, and the possible mechanisms that EVs cause the changes in mitochondrial function. Finally, we discuss the significance of this EV-mitochondria axis in hypoxic diseases.

show abstract

“…Lon levels regulate mtDNA metabolism and mitochondrial ROS production. Overexpression of Lon induces mitochondrial ROS to oxidize mtDNA, thereby allowing it to be released it into the cytoplasm [59]. As a DAMP, mtDNA can cause cellular stress.…”

Section: Ros-induced Mitochondrial Dysfunction Promotes Neurodegeneration Through the Release Of Mtdna 21 Possible Mechanisms Of Mtdna Rementioning

confidence: 99%

ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression

Zhao

Liu

et al. 2021

Antioxidants

View full text Add to dashboard Cite

One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis, is microglia-mediated and astrocyte-mediated neuroinflammation. Although inhibitions of both harmful proteins and aggregation are major treatments for neurodegenerative diseases, whether the phenomenon of non-normal protein or peptide aggregation is causally related to neuronal loss and synaptic damage is still controversial. Currently, excessive production of reactive oxygen species (ROS), which induces mitochondrial dysfunction in neurons that may play a key role in the regulation of immune cells, is proposed as a regulator in neurological disorders. In this review, we propose that mitochondrial DNA (mtDNA) release due to ROS may act on microglia and astrocytes adjacent to neurons to induce inflammation through activation of innate immune responses (such as cGAS/STING). Elucidating the relationship between mtDNA and the formation of a pro-inflammatory microenvironment could contribute to a better understanding of the mechanism of crosstalk between neuronal and peripheral immune cells and lead to the development of novel therapeutic approaches to neurodegenerative diseases.

show abstract

Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1–mediated immunoescape via STING-IFN signaling and extracellular vesicles

Cited by 89 publications

References 58 publications

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

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

The effect of extracellular vesicles on the regulation of mitochondria under hypoxia

ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression

Contact Info

Product

Resources

About