title: Aberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice.
abstract: BACKGROUND
  Asthma, a chronic inflammatory condition defined by episodic shortness of breath with expiratory wheezing and cough, is a serious health concern affecting more than 250 million persons. Genome-wide association studies have identified ORM (yeast)-like protein isoform 3 (ORMDL3) as a gene associated with susceptibility to asthma. Although its yeast ortholog is a negative regulator of de novo ceramide biosynthesis, how ORMDL3 contributes to asthma pathogenesis is not known.
  
  
  OBJECTIVE
  We sought to decipher the molecular mechanism for the pathologic functions of ORMDL3 in asthma and the relationship to its evolutionarily conserved role in regulation of ceramide homeostasis.
  
  
  METHODS
  We determined the relationship between expression of ORMDL3 and ceramide in epithelial and inflammatory cells and in asthma pathogenesis in mice.
  
  
  RESULTS
  Although small increases in ORMDL3 expression decrease ceramide levels, remarkably, higher expression in lung epithelial cells and macrophages in vitro and in vivo increased ceramide production, which promoted chronic inflammation, airway hyperresponsiveness, and mucus production during house dust mite-induced allergic asthma. Moreover, nasal administration of the immunosuppressant drug FTY720/fingolimod reduced ORMDL3 expression and ceramide levels and mitigated airway inflammation and hyperreactivity and mucus hypersecretion in house dust mite-challenged mice.
  
  
  CONCLUSIONS
  Our findings demonstrate that overexpression of ORMDL3 regulates ceramide homeostasis in cells in a complex manner and suggest that local FTY720 administration might be a useful therapeutic intervention for the control of allergic asthma.
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Clement
authors.initials: C
authors.lastname: Oyeniran
authors.affiliation: Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, Va; School of Nursing, Virginia Commonwealth University, Richmond, Va.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Sturgill
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Dorit
authors.initials: D
authors.lastname: Avni
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Michael
authors.initials: M
authors.lastname: Maceyka
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Jason
authors.initials: J
authors.lastname: Newton
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.affiliation: School of Nursing, Virginia Commonwealth University, Richmond, Va.
authors.forename: Alison
authors.initials: A
authors.lastname: Montpetit
authors.affiliation: Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Conrad
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Va. Electronic address: sspiegel@vcu.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology
chemical_list: D002518:Ceramides; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C583840:ORMDL3 protein, mouse; D000068876:Fingolimod Hydrochloride
keywords: Asthma; FTY720; ORMDL3; ceramide; house dust mite; sphingolipid
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