Abstract
Asthma and its heterogeneity change with age. Increased airspace neutrophil numbers contribute to severe steroid-resistant asthma exacerbation in the elderly, which correlates with the changes seen in adults with asthma. However, whether that resembles the same disease mechanism and pathophysiology in aged and adults is poorly understood. Here, we sought to address the underlying molecular mechanism of steroid-resistant airway inflammation development and response to corticosteroid (Dex) therapy in aged mice. To study the changes in inflammatory mechanism, we used a clinically relevant treatment model of house-dust mite (HDM)-induced allergic asthma and investigated lung adaptive immune response in adult (20–22 wk old) and aged (80–82 wk old) mice. Our result indicates an age-dependent increase in airway hyperresponsiveness (AHR), mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of HDM-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice. RNA-Seq experiments of the aged lung revealed short palate, lung, and nasal epithelial clone 1 (SPLUNC1) as one of the steroid-responsive genes, which progressively declined with age and further by HDM-induced inflammation. Moreover, we found increased glycolytic reprogramming, maturation/activation of DCs, the proliferation of OT-II cells, and Th2 cytokine secretion with recombinant SPLUNC1 (rSPLUNC1) treatment. Our results indicate a novel immunomodulatory role of SPLUNC1 regulating metabolic adaptation/maturation of DC. An age-dependent decline in the SPLUNC1 level may be involved in developing steroid-resistant airway inflammation and asthma heterogeneity.
Highlights
Asthma is a chronic disease of the upper airways that influence people differently across the lifespan, affecting 7% of the population older than 65 years [1,2,3]
Our result indicates an age-dependent increase in AHR, mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of house-dust mite (HDM)-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice
We show that the response to common aeroallergen house dust mite (HDM) and induction of airway inflammation is dysregulated with increasing age, which is manifested by steroid-resistant neutrophilic inflammation and Th1/Th17 signatures in the aged lung as compared to eosinophilic/Th2 high adult lung
Summary
Asthma is a chronic disease of the upper airways that influence people differently across the lifespan, affecting 7% of the population older than 65 years [1,2,3]. A large body of evidence from human studies and rodent models implicates that airway inflammation associated with asthma and responses to therapy in the elderly differs from that in adult asthmatic subjects [9,10,11,12]. Neutrophilic airway inflammation, similar to that noted in severe non-eosinophilic asthma, is present in the airways of older people and responds poorly to steroid therapy [7, 13, 14]. Increased airspace neutrophil numbers contribute to asthma exacerbation in the elderly, mirror the changes seen in severe asthma patients with neutrophil-predominant and mixed Th1/ Th17 cytokine signatures [3, 15,16,17]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call