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

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Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness Sidra M. Hoffman, MS, David G. Chapman, PhD, Karolyn G. Lahue, BS, Jonathon M. Cahoon, BA, Gurkiranjit K. Rattu, Nirav Daphtary, MS, Minara Aliyeva, MD, Karen A. Fortner, PhD, Serpil C. Erzurum, MD, Suzy A.A. Comhair, PhD, Prescott G. Woodruff, MD, MPH, Nirav Bhakta, MD, Anne E. Dixon, MD, Charles G. Irvin, PhD, Yvonne M.W. Janssen-Heininger, PhD, Matthew E. Poynter, PhD, Vikas Anathy, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 3, Pages 822-832.e7 (March 2016) DOI: 10.1016/j.jaci.2015.08.018 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 ERp57 levels are increased in asthmatic patients and allergen-challenged mouse epithelium. A, Representative images of human lung tissue samples obtained from the UCSF Airway Tissue Bank stained for ERp57 (red). B, Western blots of whole-lung lysates from PBS- or HDM-challenged mice probed for various UPR markers and ERp57. β-Actin was used as a control. C, Representative images of the lungs of mice challenged with PBS or HDM stained for ERp57 (red). Scale bars = 50 μm. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 HDM-induced experimental asthma is attenuated in ERp57-ablated mice. A, Ablation of ERp57 from EpCAM+ epithelial cells in mice containing the CCSP-rtTA/TetO-Cre/ERp57loxP/loxP allele. β-Actin was used as a loading control. B, HDM or PBS instillation regimen. C-G, Analysis of inflammatory and immune cells in the bronchoalveolar lavage fluid (BALF). H, Analysis of methacholine-induced AHR in mice. *P < .05, significant differences compared with PBS groups. #P < .05, significant differences compared with the HDM groups. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Deletion of ERp57 in AECs decreases levels of various cytokines and chemokines secreted from epithelial cells. A-D, ELISA for cytokines and chemokines. E, Biotin labeling of free sulfhydryl (-SH) groups with MPB. F, Western blot (WB) analysis of sulfhydryl (-SH) content of eotaxin by using MPB labeling and immunoprecipitation (IP). G, Densitometry of eotaxin-MPB in Fig 3, F. *P < .05, significant differences compared with PBS groups. #P < .05, significant differences compared with HDM groups. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Ablation of ERp57 in lung epithelial cells decreases smooth muscle hypertrophy and collagen deposition. A, IHC staining for α-SMA in PBS- and HDM-challenged lungs from Ctr and ΔERp57 mice. B, Histologic scores for α-SMA. C, Analysis of collagen deposition. *P < .05, significant differences compared with PBS groups. #P < .05, significant differences compared with HDM groups. Scale bars = 50 μm. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Ablation of ERp57 in lung epithelial cells decreases disulfide bonds (-S-S-) in profibrotic growth factors. A and B, Analysis of mRNA for epithelium-derived growth factors. C, Biotin labeling of free sulfhydryl (-SH) by MPB. D, Western blot (WB) analysis of sulfhydryl (-SH) content of periostin. E, Densitometry of periostin-MPB in Fig 5, D. F, Western blot analysis of sulfhydryl (-SH) content of EGF. G, Densitometry of the EGF-MPB in Fig 5, F. *P < .05, significant differences compared with PBS groups. #P < .05, significant differences compared with HDM groups. IP, Immunoprecipitation. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 T or B cells are not required for HDM-induced ER stress activation and collagen deposition. A, Western blot analysis for various ER stress markers and ERp57 in WT and Rag1−/− mice. β-Actin was used as a loading control. B and C, Analysis of inflammatory and immune cells in bronchoalveolar lavage fluid (BALF). D and E, Assay for production of IgG and IgE. F, Hydroxyproline assay. *P < .05, significant differences compared with PBS groups. #P < .05, significant differences compared with HDM groups. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 ERp57 levels increases are associated with increases in eosinophil counts and bronchodilator response. A, Representative images of paraffin-embedded human lung tissue samples obtained from asthmatic human subjects 1 to 3 were obtained from UCSF (Table E1), and those from subjects 4 to 6 were obtained from the Cleveland Clinic (Table E2). Tissues were stained for ERp57 (red). Scale bars = 50 μm. B, Lung tissue samples stained with secondary antibody alone. Scale bars = 50 μm. C, Semiquantitative histologic scores for ERp57. D and E, Correlations between ERp57 scores and blood eosinophil counts or bronchodilator response in nonasthmatic and asthmatic subjects. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Deletion of ERp57 has no effect on HDM-induced mucin production. A and B, Quantitative RT-PCR analysis for MUC5AC and Gob5. C, Representative histopathologic images of PAS staining of WT and ΔERp57 mice. D, PAS scoring on Ctr and ERp57-deleted mouse lungs. *P < .05, ANOVA; significant differences compared with PBS groups. Scale bars = 50 μm. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Deletion of ERp57 decreases intrinsic apoptosis in HDM-challenged mouse lungs. A, Nonreducing SDS-PAGE showing disulfide (-S-S-)–mediated Bak oligomerization in response to HDM. D, Dimer; M, monomer; T, trimer. B, Caspase-3 activity, as measured in whole-lung lysates. *P < .05, ANOVA; significant differences compared with PBS groups. #P < .05, ANOVA; significant differences compared with HDM groups (n = 7-8 mice per group). C, Representative IHC images of WT and ΔEpi-ERp57 mice challenged with HDM and stained with anti-ERp57 or anti–active caspase-3 antibody. Sequential lung sections 5 μm apart were stained. Red color represents positive staining in AECs. Scale bars = 50 μm. Journal of Allergy and Clinical Immunology 2016 137, 822-832.e7DOI: (10.1016/j.jaci.2015.08.018) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions