Referenced in: none

Automatically associated channels: ClC4 , ClCA3

Title: Modulatory role for retinoid-related orphan receptor alpha in allergen-induced lung inflammation.

Authors: Maisa Jaradat, Cliona Stapleton, Stephen L Tilley, Darlene Dixon, Christopher J Erikson, Joshua G McCaskill, Hong Soon Kang, Martin Angers, Grace Liao, Jennifer Collins, Sherry Grissom, Anton M Jetten

Journal, date & volume: Am. J. Respir. Crit. Care Med., 2006 Dec 15 , 174, 1299-309

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16973978

Abstract
Nuclear receptors play a critical role in the regulation of inflammation, thus representing attractive targets for the treatment of asthma.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.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.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.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.