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

Abstract

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 (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.

MEASUREMENTS AND MAIN 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: 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: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 174 Issue 12 Pg. 1299-309 (Dec 15 2006) ISSN: 1073-449X [Print] United States
• PMID: 16973978 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Allergens
• Ccl24 protein, mouse
• Chemokine CCL24
• Chemokine CCL3
• Chemokine CCL4
• Chemokines, CC
• Chloride Channels
• Clca3a1 protein, mouse
• Macrophage Inflammatory Proteins
• Mucin-5B
• Mucins
• Mucoproteins
• Nuclear Receptor Subfamily 1, Group F, Member 1
• Receptors, Cytoplasmic and Nuclear
• Saa3 protein, mouse
• Serum Amyloid A Protein
• Trans-Activators
• Insulin-Like Growth Factor I
• Ovalbumin

Topics

• Allergens
• Animals
• Asthma (physiopathology)
• Chemokine CCL24
• Chemokine CCL3
• Chemokine CCL4
• Chemokines, CC (genetics)
• Chloride Channels (genetics)
• Eosinophilia (etiology)
• Inflammation (physiopathology)
• Insulin-Like Growth Factor I (genetics)
• Lung (physiopathology)
• Macrophage Inflammatory Proteins (genetics)
• Mice
• Mice, Mutant Strains
• Mucin-5B
• Mucins (genetics)
• Mucoproteins (genetics)
• Nuclear Receptor Subfamily 1, Group F, Member 1
• Ovalbumin (immunology)
• Receptors, Cytoplasmic and Nuclear (deficiency, physiology)
• Serum Amyloid A Protein (genetics)
• Trans-Activators (deficiency, physiology)