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Published on: December 9, 2022
Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury
Shishi Zou1, Yifan Zuo1, Yukai Chen2
1Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Abstract:
The stimulator of interferon genes (STING) pathway serves as a crucial nexus in inflammatory responses and cell death. Despite its role in Mitochondria-Endoplasmic Reticulum Contact (MERC), the mechanistic contributions to inflammatory outcomes remain poorly understood. In clinical acute respiratory distress syndrome (ARDS) models of COVID-19 infection and animal models of LPS-induced acute lung injury (ALI), the STING pathway is closely associated with the pyroptosis pathway. The macrophage STING-N-GSDMD-mtDNA positive feedback loop, upon LPS challenge, induces inflammatory responses and pyroptosis. The GSDMD inhibitor disulfiram (DSF) specifically abrogates the N-terminal portion of GSDMD anchored to the mitochondrial membrane. Furthermore, macrophage STING mediates the direct interaction between Drp1 and N-GSDMD on mitochondrial membrane by regulating mitochondrial calcium, linking mitochondrial fission to the induction of inflammatory responses. Targeting STING-mediated mitochondrial homeostasis, both genetically and pharmacologically, may play a protective role in preventing and treating sepsis-induced acute lung injury. Overall, our study posits that STING deficiency mitigates the cooperative interaction between N-GSDMD and Drp1 in mediating mitochondrial permeabilization and rupture following LPS challenge, paving the way for further investigations into inflammation and pyroptosis.
Insights
The stimulator of interferon genes (STING) pathway links mitochondrial dynamics to inflammation and pyroptosis. Targeting STING may prevent acute lung injury by disrupting inflammatory feedback loops.
Area of Science:
- Immunology
- Cell Biology
- Mitochondrial Biology
Background:
- The stimulator of interferon genes (STING) pathway is a key regulator of inflammation and cell death.
- Its role in Mitochondria-Endoplasmic Reticulum Contact (MERC) and inflammatory outcomes requires further elucidation.
- STING pathway activation is observed in models of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).
Purpose of the Study:
- To investigate the mechanistic link between the STING pathway, mitochondrial dynamics, and pyroptosis in inflammatory responses.
- To explore the role of the STING-N-GSDMD-mtDNA feedback loop in macrophage-mediated inflammation.
- To assess the therapeutic potential of targeting STING-mediated mitochondrial homeostasis in acute lung injury.
Main Methods:
- Utilized models of COVID-19 infection and LPS-induced ALI.
- Investigated the STING-N-GSDMD-mtDNA positive feedback loop in macrophages.
- Examined the interaction between Drp1 and N-GSDMD on the mitochondrial membrane, regulated by STING and mitochondrial calcium.
- Assessed the effect of GSDMD inhibitor disulfiram (DSF).
Main Results:
- A macrophage STING-N-GSDMD-mtDNA positive feedback loop was identified, inducing inflammation and pyroptosis upon LPS challenge.
- Disulfiram (DSF) was shown to abrogate the N-terminal portion of GSDMD on the mitochondrial membrane.
- STING mediates the interaction between Drp1 and N-GSDMD, linking mitochondrial fission to inflammation via calcium regulation.
- STING deficiency reduced mitochondrial permeabilization and rupture by mitigating N-GSDMD and Drp1 interaction.
Conclusions:
- The STING pathway plays a critical role in linking mitochondrial homeostasis to inflammatory responses and pyroptosis.
- Targeting STING-mediated mitochondrial dynamics offers a potential therapeutic strategy for sepsis-induced acute lung injury.
- Understanding the STING-N-GSDMD-Drp1 axis provides insights into inflammatory mechanisms and pyroptosis induction.
