Pulmonary ORMDL3 is critical for induction of Alternaria -induced allergic airways disease

Löser, S. et al. (2017) Pulmonary ORMDL3 is critical for induction of Alternaria -induced allergic airways disease. Journal of Allergy and Clinical Immunology, 139(5), 1496-1507.e3. (doi: 10.1016/j.jaci.2016.07.033) (PMID:27623174) (PMCID:PMC5415707)

Abstract

Background: Genome-wide association studies have identified the ORM (yeast)-like protein isoform 3 (ORMDL3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. Objective: We sought to investigate in vivo the functional role of ORMDL3 in disease inception. Methods An Ormdl3-deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata was determined. An adeno-associated viral vector was also used to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 knockout mice. Results: Ormdl3 knockout mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response, and ORMDL3 was found to play a critical role in driving the activating transcription factor 6–mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum–associated degradation pathway. In addition, ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen–induced allergic airways disease. Conclusions: This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Loeser, Dr Stephan
• Authors: Löser, S., Gregory, L. G., Zhang, Y., Schaefer, K., Walker, S. A., Buckley, J., Denney, L., Dean, C. H., Cookson, W. O.C., Moffatt, M. F., and Lloyd, C. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Allergy and Clinical Immunology
• Publisher: Elsevier
• ISSN: 0091-6749
• ISSN (Online): 1097-6825
• Published Online: 10 September 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Journal of Allergy and Clinical Immunology 139(5):1496-1507.e3
• Publisher Policy: Reproduced under a Creative Commons License