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Cytoplasmic Escape of Mitochondrial DNA Mediated by Mfn2 Downregulation Promotes Microglial Activation via cGas-Sting
Fei-Long Wei1, Tian-Fu Wang1, Chao-Li Wang2
1Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
Abstract:
Neuroinflammation is associated with poor outcomes in patients with spinal cord injury (SCI). Recent studies have demonstrated that stimulator of interferon genes (Sting) plays a key role in inflammatory diseases. However, the role of Sting in SCI remains unclear. In the present study, it is found that increased Sting expression is mainly derived from activated microglia after SCI. Interestingly, knockout of Sting in microglia can improve the recovery of neurological function after SCI. Microglial Sting knockout restrains the polarization of microglia toward the M1 phenotype and alleviates neuronal death. Furthermore, it is found that the downregulation of mitofusin 2 (Mfn2) expression in microglial cells leads to an imbalance in mitochondrial fusion and division, inducing the release of mitochondrial DNA (mtDNA), which mediates the activation of the cGas-Sting signaling pathway and aggravates inflammatory response damage after SCI. A biomimetic microglial nanoparticle strategy to deliver MASM7 (named MSNs-MASM7@MI) is established. In vitro, MSNs-MASM7@MI showed no biological toxicity and effectively delivered MASM7. In vivo, MSNs-MASM7@MI improves nerve function after SCI. The study provides evidence that cGas-Sting signaling senses Mfn2-dependent mtDNA release and that its activation may play a key role in SCI. These findings provide new perspectives and potential therapeutic targets for SCI treatment.
Insights
Stimulator of interferon genes (Sting) in microglia worsens spinal cord injury (SCI) outcomes. Blocking microglial Sting improves neurological recovery by reducing inflammation and neuronal death after SCI.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Neuroinflammation significantly impacts spinal cord injury (SCI) prognosis.
- The stimulator of interferon genes (Sting) pathway is implicated in inflammatory diseases, but its role in SCI is not fully understood.
Purpose of the Study:
- To investigate the role of Sting signaling in microglial activation and its impact on neurological function after SCI.
- To explore the potential of targeting microglial Sting as a therapeutic strategy for SCI.
Main Methods:
- Examined Sting expression in microglia following SCI.
- Utilized a microglial Sting knockout model to assess functional recovery.
- Investigated the relationship between mitofusin 2 (Mfn2), mitochondrial DNA (mtDNA) release, and Sting activation.
- Developed and tested a nanoparticle-based drug delivery system (MSNs-MASM7@MI) for in vitro and in vivo SCI models.
Main Results:
- Increased Sting expression was observed in activated microglia post-SCI.
- Microglial Sting knockout improved neurological function recovery, reduced M1 microglial polarization, and alleviated neuronal death.
- Downregulation of Mfn2 led to mtDNA release, activating the cGas-Sting pathway and exacerbating SCI-related inflammation.
- The developed MSNs-MASM7@MI nanoparticles demonstrated safety and efficacy in improving nerve function in vivo.
Conclusions:
- The cGas-Sting signaling pathway, activated by Mfn2-dependent mtDNA release, plays a critical role in SCI pathogenesis.
- Targeting microglial Sting offers a promising therapeutic avenue for treating spinal cord injury.
