Allergen‐Induced Endoplasmic Reticulum Stress Regulates Lung Inflammation and Fibrosis

Abstract

BackgroundThe endoplasmic reticulum (ER) stress is known to play a critical role in many inflammatory diseases including asthma. One of the canonical responders of the ER stress, ATF6α is known to regulate inflammation in asthma. We have previously demonstrated that endobronchial biopsies from asthmatics and non‐asthmatics revealed a predominant increase in markers of ER stress in the asthmatic epithelium. These Increases positively correlated with higher eosinophil counts and bronchodilator response in asthmatics (Hoffman, S. et al., JACI, 2015‐in press). However, the mechanistic role of ER stress and ATF6α in asthma is not well understood.ObjectiveWe sought to examine the contribution of ER stress in the pathogenesis of allergic asthma, and the effect of a chemical chaperone tauroursodeoxycholic acid (TUDCA) in mitigating house dust mite (HDM)‐induced airway ER stress, inflammation and fibrosis.MethodsWe examined the markers of ER stress in asthmatic airway epithelium and utilized murine models of allergic asthma to evaluate the significance of upregulation of ER stress and evaluated the efficacy of TUDCA in mitigating allergic asthma.ResultsHDM‐challenge in mice resulted in robust increases in markers of ER stress including cleaved ATF6α as compared to Ovalbumin challenged mice. Wild type (WT) mice challenged with HDM showed a significantly higher influx of eosinophils and lymphocytes into the airways and to a lesser extent neutrophils and macrophages as compared to ATF6α−/− mice challenged with HDM. AHR measurements revealed that central airway resistance was significantly decreased in ATF6α−/− mice as compared to WT mice challenged with HDM. We also found increases in markers of fibrosis in HDM‐challenged WT mice as compared to HDM‐challenged ATF6α−/− mice.TUDCA administered during the HDM‐challenge phase (a prophylactic regimen) significantly decreased HDM‐induced markers of ER stress, airways inflammation, AHR and fibrosis as compared to control mice. Further, administration of TUDCA after the establishment of allergic airways disease, efficiently decreased HDM‐induced airways inflammation, mucus metaplasia, AHR and markers of UPR but not airway fibrotic remodeling.ConclusionOur novel results demonstrate that the markers of ER stress is increased in the airway epithelium of asthmatics and in mice with allergic airway disease. Specifically, deletion of ATF6, decreased pro‐inflammatory, fibrotic mediators, and AHR. We also demonstrate that a chemical chaperone mitigates the effects of allergen in a mouse model of asthma. These results suggest that inhibiting specific components of ER stress and strategies to utilize chemical chaperones may provide an opportunity to alleviate allergic asthma.Support or Funding InformationFunding: NIH R01 HL122383, Parker B. Francis Fellowship and Department of Pathology & Laboratory Medicine.