title: Modulatory role for retinoid-related orphan receptor alpha in allergen-induced lung inflammation.
abstract: BACKGROUND
  Nuclear receptors play a critical role in the regulation of inflammation, thus representing attractive targets for the treatment of asthma.
  
  
  OBJECTIVE
  In this study, we assess the potential regulatory function of retinoid-related orphan receptor alpha (RORalpha) in the adaptive immune response using ovalbumin (OVA)-induced airway inflammation as a model.
  
  
  METHODS
  Allergen-induced inflammation was compared between wild-type (WT) and staggerer (RORalpha(sg/sg)) mice, a natural mutant strain that is deficient in RORalpha expression.
  
  
  RESULTS
  Despite robust increases in OVA-specific IgE, RORalpha(sg/sg) mice developed significantly less pulmonary inflammation, mucous cell hyperplasia, and eosinophilia compared with similarly treated WT animals. Induction of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, was also significantly less in RORalpha(sg/sg) mice. Microarray analysis using lung RNA showed increased expression of many genes, previously implicated in inflammation, in OVA-treated WT mice. These include mucin Muc5b, the chloride channel calcium-activated 3 (Clca3), macrophage inflammatory protein (MIP) 1alpha and 1beta, eotaxin-2, serum amyloid A3 (Saa3), and insulin-like growth factor 1 (Igf1). These genes were induced to a greater extent in OVA-treated WT mice relative to RORalpha(sg/sg) mice.
  
  
  CONCLUSIONS
  Our study demonstrates that mice deficient in RORalpha exhibit an attenuated allergic inflammatory response, indicating that RORalpha plays a critical role in the development of Th2-driven allergic lung inflammation in mice, and suggests that this nuclear receptor should be further evaluated as a potential asthma target.
authors.affiliation: Cell Biology Section, Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27599-7219, USA.
authors.forename: Maisa
authors.initials: M
authors.lastname: Jaradat
authors.forename: Cliona
authors.initials: C
authors.lastname: Stapleton
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Tilley
authors.forename: Darlene
authors.initials: D
authors.lastname: Dixon
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Erikson
authors.forename: Joshua G
authors.initials: JG
authors.lastname: McCaskill
authors.forename: Hong Soon
authors.initials: HS
authors.lastname: Kang
authors.forename: Martin
authors.initials: M
authors.lastname: Angers
authors.forename: Grace
authors.initials: G
authors.lastname: Liao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Collins
authors.forename: Sherry
authors.initials: S
authors.lastname: Grissom
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
mesh_terms: D000485:Allergens; D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D054423:Chemokine CCL24; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000235:genetics; D018118:Chloride Channels / Q000235:genetics; D004802:Eosinophilia / Q000209:etiology; D007249:Inflammation / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008168:Lung / Q000503:physiopathology*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D055257:Mucin-5B; D009077:Mucins / Q000235:genetics; D009088:Mucoproteins / Q000235:genetics; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010047:Ovalbumin / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000502:physiology*; D000685:Serum Amyloid A Protein / Q000235:genetics; D015534:Trans-Activators / Q000172:deficiency / Q000502:physiology*
chemical_list: D000485:Allergens; C515485:Ccl24 protein, mouse; D054423:Chemokine CCL24; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D019402:Macrophage Inflammatory Proteins; D055257:Mucin-5B; D009077:Mucins; D009088:Mucoproteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D010047:Ovalbumin