Cellular senescence and SASP in the pathobiology of IFN-γhigh severe asthma

Abstract Background 5–10% of severe asthmatics are resistant to corticosteroids but account for 50% of health care costs spent on asthma care in the US and in Europe. 30–40% of corticosteroid-resistant severe asthmatic patients show elevated IFN-γ levels (Type1 immune response) in BAL cells that is closely associated with expression of CXCL10, a downstream IFN-γ target, and a marker of senescence associated secretory phenotype (SASP). Objective The goal of this study was to evaluate the role of SASP in severe asthma associated with an elevated level of corticosteroid-refractory IFN-γ in the airways. Methods Wild type BALB/c and IFN-γ−/− mice were sensitized with house dust mite (HDM) in combination with cdi-GMP and then subsequently repeatedly challenged with HDM. Lungs from these and control mice were subjected to either RNA-seq analysis or used for β-gal staining to demonstrate cellular senescence. Results Whole lungs from WT mice subjected to the severe asthma (SA) model demonstrated significantly higher expression of several SASP genes which included p16INK4a, CXCL10, MMP12 and IL-6 as compared to that detected in naïve WT mice. p16INK4a is a key regulator of premature cellular senescence that arrests cell cycle in G1 phase by inhibiting CDK4 and CDK6 and has been associated with corticosteroid resistance. Further, the SASP genes p16INK4a, CXCL10 and CCL8 were downregulated in the absence of IFN-γ suggesting a possible role of elevated IFN-γ in SASP induction. The lung sections from mice subjected to the SA model showed increased numbers of b-gal positive cells as compared to that found in control mice. Conclusion SASP may underlie persistent inflammation and corticosteroid resistance observed in a subset of severe asthma patients.