Interferon Mediated Bronchial Epithelium Cellular Senescence in Chronic Obstructive Pulmonary Disease.

Abstract

Cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The mechanisms of senescence in the bronchial epithelium, however, remain largely unknown. This study aimed to elucidate whether cellular senescence in COPD epithelial cells contributes to the pathogenesis of the disease and investigated the potential molecular mechanisms involved. Single cell RNA sequencing was performed on well differentiated primary bronchial epithelial cells from COPD and healthy subjects. We evaluated the abundance and distribution of senescence markers in key epithelial differentiated subtypes and senescence-associated secretory phenotype involved in airway epithelial dysfunction. The effects of interferon pathway inhibitors on cellular senescence were also investigated. There was increased expression of cellular senescence genes in the COPD cohort, which was predominantly in basal and club cells. Enhanced expression of cellular senescence markers, p16 and p21, was observed in COPD cultures, which was histologically confirmed in the lung tissue of COPD patients. There was also a notable increase in IFN-β and IFN-γ. Senescence associated secretory phenotype productions were increased in COPD and was attenuated by JAK-STAT or cGAS-STING pathway inhibitors (baricitinib or C-176). These inhibitors also effectively suppressed expression of senescence markers. COPD bronchial epithelium displays a senescence driven phenotype which is mediated by type I/II interferons. Inhibition of JAK-STAT or STING-cGAS interferon pathways may represent targets to alleviate cellular senescence and chronic inflammation in COPD.