Rhinitis, sinusitis, and upper airway disease
Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

https://doi.org/10.1016/j.jaci.2015.08.018Get rights and content

Background

Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum–localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated 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 epithelium–specific ERp57 in the pathogenesis of allergic asthma.

Methods

We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57.

Results

Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite–challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite–induced endoplasmic reticulum stress and airways fibrosis.

Conclusions

Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype.

Section snippets

Human samples

Lung tissues from patients with physician-diagnosed asthma and nonasthmatic subjects were obtained from the Department of Medicine of the University of California, San Francisco (UCSF), and the Department of Pathobiology of the Cleveland Clinic. The Institutional Review Boards of the University of California and Cleveland Clinic approved provision of deidentified materials for research at the University of Vermont. All subjects were nonsmokers defined as never smokers or former smokers with no

ERp57 levels are increased in human subjects with asthma and mice with allergic airways disease

To investigate whether ERp57 expression is altered in the lung during asthma pathogenesis, we stained bronchial biopsy samples from nonasthmatic and asthmatic subjects (who refrained from inhaled corticosteroids for 6 weeks before the study) for ERp57 by means of immunohistochemistry. Marked increases in ERp57 levels were observed in lung samples from asthmatic patients (n = 9) compared with nonasthmatic subjects (n = 9; Fig 1, A, and see Fig E1, A and C, and Table E1, Table E2 in this

Discussion

Our results show that asthmatic patients exhibit a marked increase in ERp57 levels compared with those in nonasthmatic subjects, predominantly in the lung epithelium. Using a murine model of allergic asthma, we demonstrated that epithelium-specific upregulation of PDI-ERp57 modulates allergen-induced inflammation, AHR, and airways fibrosis in the lung. Furthermore, we also report that adaptive immune responses are dispensable for the development of allergen-induced UPR, upregulation of ERp57,

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  • Cited by (0)

    Supported by National Institutes of Health (NIH) grant R01HL122383, a Parker B. Francis Fellowship, and American Thoracic Society unrestricted grant, the AAFA-Sheldon C. Siegel award, the UVM-College of Medicine Internal Grant Program to V.A. and NIH grant R01HL079331 to Y.M.W.J.-H. D.G.C. is a recipient of a CJ Martin Fellowship from the national Health and Medical Research Council of Australia (1053790). S.C.E. and S.A.A.C. are supported by NIH grants HL103453 and HL081064.

    Disclosure of potential conflict of interest: S. M. Hoffman has received a grant from the National Institutes of Health (NIH). G. K. Rattu has received a Summer Research Award from the University of Vermont and received payment for research from that award. K. A. Fortner has received grants from the NIH and is employed by the University of Vermont. S. C. Erzurum has received grants from the NIH, is the chair of the American Board of Internal Medicine Pulmonary Disease Board, and has received honoraria as Councilor for the Association of American Physicians. P. G. Woodruff has received grants from Genentech and the NIH; has received personal fees from Genentech, Johnson and Johnson, Roche, Neostem, Astra Zeneca, and Novartis; and has a patent pending for 12/935822 “Compositions and methods for treating and diagnosing asthma.” N. Bhakta has received grants from Genentech. A. E. Dixon has consultant arrangements with Roche and has received grants from the NIH and Pfizer. C. G. Irvin has received a grant from the NIH. Y. M. W. Janssen-Heininger has received a grant from the NIH (HLR01079331). M. E. Poynter has received grants from NIH, the Asthma and Allergy Foundation of America, and the Flight Attendant Medical Research Institute. V. Anathy has received grants from the NIH (R01HL122383), the Parker B. Francis Foundation, the American Thoracic Society, and the Asthma and Allergy Foundation of America; has received travel support from the Parker B. Francis Foundation; and is employed by the University of Vermont. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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