Sidra M Hoffman1, David G Chapman2, Karolyn G Lahue1, Jonathon M Cahoon3, Gurkiranjit K Rattu3, Nirav Daphtary4, Minara Aliyeva4, Karen A Fortner4, Serpil C Erzurum5, Suzy A A Comhair5, Prescott G Woodruff6, Nirav Bhakta6, Anne E Dixon4, Charles G Irvin4, Yvonne M W Janssen-Heininger1, Matthew E Poynter4, Vikas Anathy7. 1. Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT. 2. Department of Medicine, University of Vermont College of Medicine, Burlington, VT; Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia. 3. Department of Biology, University of Vermont, Burlington, VT. 4. Department of Medicine, University of Vermont College of Medicine, Burlington, VT. 5. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. 6. Department of Medicine, University of California, San Francisco, Calif. 7. Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT. Electronic address: Vikas.anathy@med.uvm.edu.
Abstract
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.
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.
Authors: Anne-Karina T Perl; Susan E Wert; David E Loudy; Zhengyuan Shan; Paula A Blair; Jeffrey A Whitsett Journal: Am J Respir Cell Mol Biol Date: 2005-07-29 Impact factor: 6.914
Authors: Clement Oyeniran; Jamie L Sturgill; Nitai C Hait; Wei-Ching Huang; Dorit Avni; Michael Maceyka; Jason Newton; Jeremy C Allegood; Alison Montpetit; Daniel H Conrad; Sheldon Milstien; Sarah Spiegel Journal: J Allergy Clin Immunol Date: 2015-04-02 Impact factor: 10.793
Authors: Timothy D Le Cras; Thomas H Acciani; Elizabeth M Mushaben; Elizabeth L Kramer; Patricia A Pastura; William D Hardie; Thomas R Korfhagen; Umasundari Sivaprasad; Mark Ericksen; Aaron M Gibson; Michael J Holtzman; Jeffrey A Whitsett; Gurjit K Khurana Hershey Journal: Am J Physiol Lung Cell Mol Physiol Date: 2010-12-17 Impact factor: 5.464
Authors: Sidra M Hoffman; Jane E Tully; James D Nolin; Karolyn G Lahue; Dylan H Goldman; Nirav Daphtary; Minara Aliyeva; Charles G Irvin; Anne E Dixon; Matthew E Poynter; Vikas Anathy Journal: Respir Res Date: 2013-12-24
Authors: Emily M Nakada; Nirav R Bhakta; Bethany R Korwin-Mihavics; Amit Kumar; Nicolas Chamberlain; Sierra R Bruno; David G Chapman; Sidra M Hoffman; Nirav Daphtary; Minara Aliyeva; Charles G Irvin; Anne E Dixon; Prescott G Woodruff; Shantu Amin; Matthew E Poynter; Dhimant H Desai; Vikas Anathy Journal: JCI Insight Date: 2019-05-02
Authors: Jalahalli M Siddesha; Emily M Nakada; Bethany R Mihavics; Sidra M Hoffman; Gurkiranjit K Rattu; Nicolas Chamberlain; Jonathon M Cahoon; Karolyn G Lahue; Nirav Daphtary; Minara Aliyeva; David G Chapman; Dhimant H Desai; Matthew E Poynter; Vikas Anathy Journal: Am J Physiol Lung Cell Mol Physiol Date: 2016-05-06 Impact factor: 5.464
Authors: Nirav R Bhakta; Stephanie A Christenson; Srilaxmi Nerella; Owen D Solberg; Christine P Nguyen; David F Choy; Kyle L Jung; Suresh Garudadri; Luke R Bonser; Joshua L Pollack; Lorna T Zlock; David J Erle; Charles Langelier; Joseph L Derisi; Joseph R Arron; John V Fahy; Prescott G Woodruff Journal: Am J Respir Crit Care Med Date: 2018-02-01 Impact factor: 21.405
Authors: Xi Qian; Reem Aboushousha; Cheryl van de Wetering; Shi B Chia; Eyal Amiel; Robert W Schneider; Jos L J van der Velden; Karolyn G Lahue; Daisy A Hoagland; Dylan T Casey; Nirav Daphtary; Jennifer L Ather; Matthew J Randall; Minara Aliyeva; Kendall E Black; David G Chapman; Lennart K A Lundblad; David H McMillan; Anne E Dixon; Vikas Anathy; Charles G Irvin; Matthew E Poynter; Emiel F M Wouters; Pamela M Vacek; Monique Henket; Florence Schleich; Renaud Louis; Albert van der Vliet; Yvonne M W Janssen-Heininger Journal: J Allergy Clin Immunol Date: 2017-11-03 Impact factor: 10.793
Authors: Prabuddha S Pathinayake; Alan C-Y Hsu; David W Waters; Philip M Hansbro; Lisa G Wood; Peter A B Wark Journal: Front Immunol Date: 2018-02-06 Impact factor: 7.561