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Published ahead of print on September 14, 2006, doi:10.1164/rccm.200510-1672OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 12, December 2006, 1299-1309

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Submitted on October 26, 2005
Accepted on September 14, 2006

Modulatory Role for Retinoid-related Orphan Receptor {alpha} (ROR{alpha}) in Allergen-induced Lung Inflammation

Maisa Jaradat1, Cliona Stapleton1, Stephen L Tilley2, Darlene Dixon3, Christopher J Erikson2, Joshua G McCaskill2, Hong Soon Kang1, Martin Angers1, Grace Liao1, Jennifer Collins4, Sherry Grissom4, and Anton M Jetten1*

1 Laboratory of Respiratory Biology, Cell Biology Section, National Institutes of Health, National Institute of Environmental Health Sciences, Division of Intramural Research, Research Triangle Park, North Carolina, USA, 2 Department of Medicine, Pulmonary Immunobiology Laboratory, University of North Carolina, Division of Pulmonary and Critical Care Medicine, Chapel Hill, North Carolina, USA, 3 Laboratory of Experimental Pathology, National Institutes of Health, National Institute of Environmental Health Sciences, Division of Intramural Research, Research Triangle Park, North Carolina, USA, 4 Microarray Group, National Institutes of Health, National Institute of Environmental Health Sciences, Division of Intramural Research, Research Triangle Park, North Carolina, USA

* To whom correspondence should be addressed. E-mail: jetten{at}niehs.nih.gov.

Rationale: 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} (ROR{alpha}) 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 (ROR{alpha}sg/sg) mice, a natural mutant strain that is deficient in ROR{alpha} expression. Measurements and Main Results: Despite robust increases in OVA-specific IgE, ROR{alpha}sg/sg mice developed significantly less pulmonary inflammation, mucus cell hyperplasia, and eosinophilia compared to similarly treated WT animals. Induction of Th2 cytokines, including interleukins 4, 5, and 13, was also significantly less in ROR{alpha}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) 1{alpha} and 1{beta}, 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 ROR{alpha}sg/sg mice. Conclusions: Our study demonstrates that mice deficient in ROR{alpha} exhibit an attenuated allergic inflammatory response, indicating that ROR{alpha} 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.
Key words: asthma, lung, nuclear receptor, inflammation




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