title: ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma.
abstract: Orosomucoid-like (ORMDL)3 has been strongly linked with asthma in genetic association studies. Because allergen challenge induces lung ORMDL3 expression in wild-type mice, we have generated human ORMDL3 zona pellucida 3 Cre (hORMDL3(zp3-Cre)) mice that overexpress human ORMDL3 universally to investigate the role of ORMDL3 in regulating airway inflammation and remodeling. These hORMDL3(zp3-Cre) mice have significantly increased levels of airway remodeling, including increased airway smooth muscle, subepithelial fibrosis, and mucus. hORMDL3(zp3-Cre) mice had spontaneously increased airway responsiveness to methacholine compared to wild-type mice. This increased airway remodeling was associated with selective activation of the unfolded protein response pathway transcription factor ATF6 (but not Ire1 or PERK). The ATF6 target gene SERCA2b, implicated in airway remodeling in asthma, was strongly induced in the lungs of hORMDL3(zp3-Cre) mice. Additionally, increased levels of expression of genes associated with airway remodeling (TGF-β1, ADAM8) were detected in airway epithelium of these mice. Increased levels of airway remodeling preceded increased levels of airway inflammation in hORMDL3(zp3-Cre) mice. hORMDL3(zp3-Cre) mice had increased levels of IgE, with no change in levels of IgG, IgM, and IgA. These studies provide evidence that ORMDL3 plays an important role in vivo in airway remodeling potentially through ATF6 target genes such as SERCA2b and/or through ATF6-independent genes (TGF-β1, ADAM8).
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.forename: Andrew
authors.initials: A
authors.lastname: Beppu
authors.forename: James L
authors.initials: JL
authors.lastname: Mueller
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.forename: Arvin B
authors.initials: AB
authors.lastname: Tam
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Doherty
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McGeough
authors.forename: Carla A
authors.initials: CA
authors.lastname: Pena
authors.forename: Maho
authors.initials: M
authors.lastname: Suzukawa
authors.forename: Maho
authors.initials: M
authors.lastname: Niwa
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D056151:Airway Remodeling / Q000235:genetics* / Q000276:immunology*; D000485:Allergens / Q000276:immunology; D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D001249:Asthma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced; D019742:Chemokines, CC / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D019076:Transgenes; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D000485:Allergens; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016207:Cytokines; D007073:Immunoglobulin E; D008565:Membrane Proteins; D016210:Methacholine Chloride; D010047:Ovalbumin; D019892:eIF-2 Kinase; C464399:ORMDL3 protein, human