MTOR Suppresses Cigarette Smoke-Induced Airway Inflammation and MMP12 Expression in Macrophage in Chronic Obstructive Pulmonary Disease

Abstract

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.

Keywords:

• matrix metalloproteinase 12
• MMP12
• pulmonary emphysema
• cigarette smoke
• CS
• mechanistic target of rapamycin
• MTOR

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

This work was supported by the General Project of National Natural Science Foundation of China (31970826 to Zhihua Chen), the Major project of Zhejiang Natural Science Foundation (LD21H010001 to Zhihua Chen), the Key Project of National Natural Science Foundation of China (81930003 to Huahao Shen), the Youth Project of National Natural Science Foundation of China (81800033 to Jiesen Zhou and 82100042 to Zhouyang Li), the General Project of National Natural Science Foundation of China (82070047 to Yong Wang).