CARM1 regulates senescence during airway epithelial cell injury in COPD pathogenesis

Abstract

Chronic obstructive pulmonary disease (COPD) is a life-threatening lung disease. Although cigarette smoke was considered the main cause of development, the heterogeneous nature of the disease leaves it unclear whether other factors contribute to the predisposition or impaired regeneration response observed. Recently, epigenetic modification has emerged to be a key player in the pathogenesis of COPD. The addition of methyl groups to arginine residues in both histone and nonhistone proteins by protein arginine methyltransferases (PRMTs) is an important posttranslational epigenetic modification event regulating cellular proliferation, differentiation, apoptosis, and senescence. Here, we hypothesize that coactivator-associated arginine methyltransferase-1 (CARM1) regulates airway epithelial cell injury in COPD pathogenesis by controlling cellular senescence. Using the naphthalene (NA)-induced mouse model of airway epithelial damage, we demonstrate that loss of CC10-positive club cells is accompanied by a reduction in CARM1-expressing cells of the airway epithelium. Furthermore, Carm1 haploinsuffficent mice showed perturbed club cell regeneration following NA treatment. In addition, CARM1 reduction led to decreased numbers of antisenescent sirtuin 1-expressing cells accompanied by higher p21, p16, and β-galactosidase-positive senescent cells in the mouse airway following NA treatment. Importantly, CARM1-silenced human bronchial epithelial cells showed impaired wound healing and higher β-galactosidase activity. These results demonstrate that CARM1 contributes to airway repair and regeneration by regulating airway epithelial cell senescence.

TET2 stabilized by deubiquitinase USP21 ameliorates cigarette smoke-induced apoptosis in airway epithelial cells

“…Coactivator-associated arginine methyltransferase-1 (CARM1) regulates airway epithelial cell injury in COPD progression. 29 Complete loss of CARM1 leads to disrupted differentiation and maturation of epithelial cells and promote the development of emphysema. 30 Our previous work also shown that dysregulation of DNA methyltransferase DNMT1 involved in the pathogenesis of COPD.…”

Nicotine promotes chronic obstructive pulmonary disease via inducing pyroptosis activation in bronchial epithelial cells

“…Cigarette smoke can cause inflammation, which is an important injury factor in lung diseases such as COPD ( 41 ). The damage to the lungs caused by cigarette smoke is most directly reflected in the injury of bronchial epithelial cells and alveolar epithelial cells ( 42 ). Bronchial epithelial cells are one of the key cell types that mediate inflammation and the 16HBE cell line is a common cell line used to study COPD pathogenesis in vitro .…”

RSV attenuates epithelial cell restitution by inhibiting actin cytoskeleton-dependent cell migration

“…The naphthalene-induced airway injury used in this study results in specific ablation of club cells of the airway only and may not fully recapitulate an epithelial lesion. However, previous studies have demonstrated that club cells account for 15% of proliferating airway epithelial cells in the terminal bronchioles and, thus, are vital for maintaining the distal airways after injury ( 69 , 96 ). Therefore, we consider naphthalene a suitable model for studying airway injury in a murine model.…”