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MTOR Suppresses Cigarette Smoke-Induced Airway Inflammation and MMP12 Expression in Macrophage in Chronic Obstructive
Lingling Dong1, Yong Wang1, Haipin Chen1
1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Background:
Macrophage-derived matrix metalloproteinase 12 (MMP12) can cause destruction of lung tissue structure and plays a significant role in the development and progression of chronic obstructive pulmonary disease (COPD). MTOR is a serine/threonine kinase that plays a crucial role in cell growth and metabolism. The activity of MTOR in the lung tissues of COPD patients also shows significant changes. However, it is unclear whether MTOR can regulate the development and progression of COPD by controlling MMP12. This study primarily investigates whether MTOR in macrophages can affect the expression of MMP12 and participate in the progression of COPD.
Methods:
We tested the changes in MTOR activity in macrophages exposed to cigarette smoke (CS) both in vivo and in vitro. Additionally, we observed the effect of MTOR on the expression of MMP12 in macrophages and on lung tissue inflammation and structural damage in mice, both in vivo and in vitro, using MTOR inhibitors or gene knockout mice. Finally, we combined inhibitor treatment with gene knockout to demonstrate that MTOR primarily mediates the expression of MMP12 through the NF-κB signaling pathway.
Results:
Exposure to CS can enhance MTOR activity in mouse alveolar macrophages. Inhibiting the activity of MTOR or suppressing its expression leads to increased expression of MMP12. Myeloid-specific knockout of MTOR expression can promote the occurrence of CS-induced pulmonary inflammation and emphysema in mice. Inhibiting the activity of NF-κB can eliminate the effect of MTOR on MMP12.
Conclusion:
Macrophage MTOR can reduce the expression of MMP12 by inhibiting NF-κB, thereby inhibiting the occurrence of COPD inflammation and destruction of lung tissue structure. Activating the activity of macrophage MTOR may be beneficial for the treatment of COPD.
Insights
Macrophage MTOR regulates MMP12 expression, impacting COPD progression. Activating MTOR in macrophages may offer a therapeutic strategy for COPD by reducing lung tissue destruction.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Molecular Biology
Background:
- Macrophage-derived matrix metalloproteinase 12 (MMP12) contributes to lung tissue destruction in chronic obstructive pulmonary disease (COPD).
- Mammalian target of rapamycin (MTOR) activity is altered in COPD lungs, but its role in regulating MMP12 and COPD pathogenesis is unclear.
Purpose of the Study:
- To investigate if MTOR in macrophages influences MMP12 expression and COPD progression.
- To elucidate the mechanism by which MTOR affects MMP12 and COPD.
Main Methods:
- Assessed MTOR activity in macrophages exposed to cigarette smoke (CS) in vivo and in vitro.
- Utilized MTOR inhibitors and myeloid-specific MTOR knockout mice to study MTOR's effect on MMP12 expression, lung inflammation, and emphysema.
- Investigated the role of the NF-κB signaling pathway in mediating MTOR's effect on MMP12.
Main Results:
- CS exposure increased MTOR activity in mouse alveolar macrophages.
- MTOR inhibition or suppression led to increased MMP12 expression.
- MTOR deficiency in myeloid cells exacerbated CS-induced lung inflammation and emphysema.
- NF-κB inhibition abolished MTOR's effect on MMP12.
Conclusions:
- Macrophage MTOR suppresses MMP12 expression via NF-κB inhibition, thereby mitigating COPD-related inflammation and lung tissue damage.
- Activating macrophage MTOR presents a potential therapeutic avenue for COPD treatment.
