DNA dioxygenases TET2 deficiency promotes cigarette smoke induced chronic obstructive pulmonary disease by inducing ferroptosis of lung epithelial cell
Zihang Zeng,
Tiao Li,
Xiangming Liu,
Yiming Ma,
Lijuan Luo,
ZuLi Wang,
Zhiqi Zhao,
Herui Li,
Xue He,
Huihui Zeng,
Yongguang Tao,
Yan Chen
Affiliations
Zihang Zeng
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
Tiao Li
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China; Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
Xiangming Liu
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
Yiming Ma
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
Lijuan Luo
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
ZuLi Wang
Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Changsha, China
Zhiqi Zhao
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
Herui Li
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
Xue He
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
Huihui Zeng
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China
Yongguang Tao
Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, Hunan, 410078, China; NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China
Yan Chen
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China; Research Unit of Respiratory Disease, Central South University, Changsha, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, China; Corresponding author. Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China.
Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality currently. Long-term exposure of cigarette smoke (CS) inducing persistent inflammation, small airway remodeling and emphysematous lung are the distinguishing features of COPD. Ferroptosis, occurred in lung epithelial cells has recently been reported to be associated with COPD pathogenesis. DNA dioxygenase ten-eleven translocation 2 (TET2) is an important demethylase and its genetic mutation is associated with low forced expiratory volume in 1 s (FEV1) of lung function. However, its role in COPD remains elusive. Here, we found that TET2 regulates CS induced lipid peroxidation through demethylating glutathione peroxidase 4 (GPx4), thus alleviating airway epithelial cell ferroptosis in COPD. TET2 protein levels were mainly reduced in the airway epithelia of COPD patients, mouse models, and CS extract-treated bronchial epithelial cells. The deletion of TET2 triggered ferroptosis and further exaggerated CS-induced airway remodeling, inflammation, and emphysema in vivo. Moreover, we demonstrated that TET2 silencing intensified ferroptosis, while TET2 overexpression inhibited ferroptosis in airway epithelial cell treated with CSE. Mechanically, TET2 protected airway epithelial cells from CS-induced lipid peroxidation and ferroptosis through demethylating the promoter of glutathione peroxidase 4 (GPx4). Finally, co-administration of methylation inhibitor 5′-aza-2′-deoxycytidine (5-AZA) and the antioxidant N-acetyl-cysteine (NAC) have more protective effects on CS-induced COPD than either administration alone. Overall, our study reveals that TET2 is an essential modulator in the lipid peroxidation and ferroptosis of airway epithelial cell, and could act as a potential therapeutic target for CS-induced COPD.
