Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

Abstract

Background Evidence for association between asthma and the unfolded protein response (UPR) is emerging. ERp57 is an ER localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is up regulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown. Objectives Here, we sought to examine the contribution of airway epithelial-specific ERp57 in the pathogenesis of allergic asthma. Methods We examined the expression of ERp57 in human asthmatic airway epithelium and utilized murine models of allergic asthma to evaluate the relevance of epithelial- specific ERp57. Results Lung biopsies from asthmatics and non-asthmatics revealed a predominant increase in ERp57 in asthmatic epithelium. Deletion of ERp57 resulted in a significant decreases in the inflammatory cells and airways resistance in a murine model of allergic asthma. We further observed that disulfide bridges in eotaxin, EGF and periostin were also decreased in the lungs of HDM-challenged ERp57 deleted mice. Fibrotic markers such as collagen and αSMA were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for HDM-induced ER stress and airways fibrosis. Conclusions Here we show that ERp57 is increased in the airway epithelium of asthmatics and in mice with allergic airways disease. ERp57 increase is associated with redox modification of pro- inflammatory, apoptotic and fibrotic mediators, and contribute to airways hyperresposiveness (AHR). The strategies to inhibit ERp57 specifically within the airways epithelium may provide an opportunity to alleviate allergic asthma phenotype.

Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease

“…Moreover, the activation of XBP-1 has been shown to increase the levels of IL-6 in alveolar macrophages from patients with cystic fibrosis (39). In addition, our laboratory has demonstrated that the HDM-induced ER stress is linked to increased CCL20 and IL-6 in wild-type mice (23). Furthermore, the proinflammatory cytokines (IL-6), Th2 cytokines (IL-13 and IL-4), Th17 cytokines (IL-17A), and chemokines, including CCL20, KC, and G-CSF, have been shown to play a critical role in the pathogenesis of allergic airway disease (1,7,18,47,48,64).…”

“…Airway remodeling is characterized by abnormal subepithelial collagen deposition along airway walls, smooth muscle hypertrophy, epithelial cell hyperplasia, mucus metaplasia, and basement membrane thickening (22). Increased levels of the profibrotic growth factor TGF-␤, collagen, and ␣-SMA in the lung drive airway fibrosis (23,56). Our results showed that TUDCA in both the preventive regimen and therapeutic regimen with subsequent HDM rechallenge significantly decreased collagen/hydroxyproline content and peribronchiolar fibrosis in the lungs of HDM-challenged mice.…”

“…Bronchoalveolar lavage fluid (BALF) was collected by lavaging lungs with 1.0 ml of sterile PBS. Total and differential cell counts were performed as previously described (23). Briefly, cells were isolated by centrifugation, and total cell counts were enumerated using the Advia 120 Automated Hematology Analyzer System.…”

“…Paraffin blocks were cut into 5-m sections and mounted to slides. Immunohistochemistry was performed on the paraffin-embedded lung sections to determine the ␣-smooth muscle actin (␣-SMA) content, as described previously (23). Images were captured at a magnification of ϫ20 using an Olympus BX50 light microscope and analyzed for quantifying ␣-SMA-positive area of airway using MetaMorph software.…”

“…Our group has previously shown that house dust mite (HDM) induces components of ER stress, including activating transcription factor 6 (ATF6) ␣ and endoplasmic reticulum resident protein 57 (ERp57), in airway epithelial cells, both in vitro and in vivo (24). Moreover, small-interfering RNAmediated knockdown of ATF6␣ and ERp57 in mice during the development of allergic airway pathophysiology resulted in a decrease in ER stress, inflammation, airway fibrosis, and AHR, the fundamental features of allergic airway disease in mice, indicating the significant role of these ER stress mediators in the development of allergic airway disease (23,24). Furthermore, increases in ERp57 level in the airway epithelium from asthmatic patients compared with healthy normal individuals, and the decrease in HDM-induced airway inflammation, fibrosis, and AHR, in ERp57-deficient mice compared with wildtype mice, supports the significance of ER stress in the development of allergic airway diseases (23).…”