Pulmonary ORMDL3 is critical for induction of Alternaria-induced allergic airways disease.
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.
Inflammation, Repair & Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Stephan
S
Löser
Inflammation, Repair & Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Lisa G
LG
Gregory
Genomic Medicine Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Youming
Y
Zhang
Inflammation, Repair & Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Katrein
K
Schaefer
Inflammation, Repair & Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Simone A
SA
Walker
Inflammation, Repair & Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
James
J
Buckley
Inflammation, Repair & Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Laura
L
Denney
Inflammation, Repair & Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Charlotte H
CH
Dean
Genomic Medicine Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
William O C
WOC
Cookson
Genomic Medicine Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Miriam F
MF
Moffatt
Inflammation, Repair & Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. Electronic address: c.lloyd@imperial.ac.uk.
Clare M
CM
Lloyd
D000485:Allergens / Q000276:immunology; D000528:Alternaria / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D008168:Lung / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020545:Respiratory Mucosa / Q000276:immunology; D014527:Uric Acid / Q000378:metabolism
D000485:Allergens; D008565:Membrane Proteins; C583840:ORMDL3 protein, mouse; D014527:Uric Acid
Alternaria; ORMDL3; asthma; unfolded protein response; uric acid