Inflammasome activation and metabolic remodelling in p16‐positive aging cells aggravates high‐fat diet‐induced lung fibrosis by inhibiting NEDD4L‐mediated K48‐polyubiquitin‐dependent degradation of SGK1

作者：Xin Gu, Haoyu Meng, Chengyi Peng, Shiyu Lin, Baihong Li, Lin Zhao, Xue Yang, Guangyan Wang, Wenyuan Cai, Jiawen Zhou, Shuiyuan Liu, Peng Wu, Yingqiang Du, Jianliang Jin, Xiaoyan Wang · 发表于：Clinical and Translational Medicine · 年份：2023 · DOI：10.1002/ctm2.1308 · 被引用次数：25 · 研究领域：Telomeres, Telomerase, and Senescence、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Chronic Obstructive Pulmonary Disease (COPD) Research

BACKGROUND: Chronic changes caused by a high-fat diet (HFD) may be associated with weakened lung function in obese patients. However, few studies have focused on the role of senescent cells in HFD-induced pulmonary fibrosis. This study aimed to determine whether (i) obesity causes the accumulation of aging cells in the lungs, (ii) p16 accumulation in aging epithelial cells or fibroblasts exacerbates long-term HFD-induced senescence-associated pulmonary fibrosis (SAPF) and (iii) p16 deletion or clearance of aging cells ameliorates HFD-induced SAPF through inactivation of the inflammasome and metabolic remodelling. METHODS: were fed a HFD to induce obesity, and the effects of treatment with the senolytic drug ABT263 or the SGK1 specific inhibitor EMD638683 on fibrosis, inflammaging, gene expression, integrin-inflammasome signalling and metabolism were examined. A549 and IMR-90 cells were transduced with p16-overexpressing adenovirus, and treated with palmitic and oleic acids (P&O) to induce steatosis in vitro. RESULTS: We found that long-term HFD promoted the expression of p16 and the increase of senescent cells in the lung. P16 knockout or ABT263 treatment alleviated pulmonary fibrosis, the increase of senescent cells and senescence-associated secretory phenotype (SASP) in HFD-fed mice, as well as in P&O-treated A549 and IMR-90 cells. RNA sequencing and bioinformatics analyses revealed that p16 knockout inhibited activation of the integrin-inflammasome pathway and cellular gly...