ITGB4 deficiency induces senescence of airway epithelial cells through p53 activation

Abstract

Aging is characterized by a progressive loss of physiological integrity, leading to impaired organ function and, ultimately, increased vulnerability to death. Many complex diseases are related to aging, including asthma. In the lung, the airway epithelium serves as the first barrier to prevent the access of inspired external stimuli and dictates the initial stress responses. Notably, in the airway mucosa of asthma patients, an increase in senescent airway epithelial cells has been detected. Although it has been speculated that the senescence of airway epithelial cells could increase asthma susceptibility and aggravate asthma severity, the role of cell senescence in the development of asthma remains unclear. Integrin β4 (ITGB4) is a structural adhesion molecule with complex physiological functions that is downregulated in airway epithelial cells of asthma patients. This study demonstrates that the expression of ITGB4 in airway epithelial cells is downregulated significantly under oxidative stress or upon inflammatory stimulation. Moreover, we show that ITGB4 deficiency induces the senescence of airway epithelial cells through the activation of the p53 pathway both in vitro and in vivo. Together, our results demonstrate that airway epithelial senescence induced by ITGB4 deficiency after oxidative stress or inflammatory stimulation may be involved in the pathogenesis of asthma. Understanding the contribution of ITGB4 deficiency to the senescence of airway epithelial cells in asthma patients may provide new therapeutic approaches for the treatment of asthma.

Potential Role of Cellular Senescence in Asthma

“…In IPF, we could find out a lot of gene mutations correlating to the premature aging of epithelial cells (Richeldi et al, 2017), while those gene mutations haven't been reported in asthma. Instead, according to current studies, ITGB4 might be a pivotal gene to link epithelial cell senescence and the development of asthma (Liu et al, 2010a,b;Yuan et al, 2019), while it has not been demonstrated in COPD and IPF.…”

“…ITGB4 was also found to be decreased in asthmatic patients (Liu et al, 2010b). Deficiency of ITGB4 could result in cellular senescence in airway epithelial cells through p53 signaling pathway (Yuan et al, 2019). Besides, ITGB4 deficiency could also result in severe airway inflammation and airway hyperresponsiveness in asthma (Liu et al, 2010a).…”

Variable Expressed Methylation Sites of Aging-related Genes in Asthma

“…Of particular note is the potential role of aging in the parthenogenesis of asthma [28,29]. Many studies have demonstrated the exist of aging structural cells, immune cells and mesenchymal cells in asthmatic lung although the speci c role of aging cells in asthma is still not fully understood [20,30,31]. Meanwhile, some related studies have also con rmed the different expression of aging-related genes (such as TP53 and FOXO3) in the development of respiratory diseases [32,33].…”

“…Total mRNA was puri ed from peripheral blood cells using Trizol (Invitrogen) and quanti ed by an ultraviolet spectrophotometer (Thermo Fisher Scienti c, USA) [20]. 1μg RNA was reverse transcribed into cDNA using Reverse Transcriptase Kit (Qiagen, Netherlands) accordance to the manufacturer's instructions [21].…”

Variable expressed methylation sites of aging-related genes in asthma

“…Total mRNA was puri ed from peripheral blood cells using Trizol (Invitrogen) and quanti ed by an ultraviolet spectrophotometer (Thermo Fisher Scienti c, USA) [20]. 1 µg RNA was reverse transcribed into cDNA using Reverse Transcriptase Kit (Qiagen, Netherlands) accordance to the manufacturer's instructions [21].…”