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Transcriptional Analyses before and after Suppression of Immediate Hypersensitivity Reactions by CCR3 Blockade in Eyes with Experimental Allergic Conjunctivitis

¹From the Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Totttori, Japan; and the ²Research Division, Mitsubishi Tanabe Pharma Co., Yokohama, Japan.

PURPOSE. To characterize the transcriptome of allergic conjunctivitis mediated by eosinophil-related chemokine receptor CCR3 and to identify a candidate for possible therapeutic intervention in eosinophilic inflammation of the eye.

METHODS. Mice were sensitized to ragweed pollen, and allergic conjunctivitis was induced by an allergen challenge. The induction of allergic conjunctivitis was used to determine whether an inhibition of CCR3 would suppress eosinophilic inflammation and the allergen-induced immediate hypersensitivity reaction. In addition, sensitized mice were treated with a CCR3 antagonist or an anti–CCR3 antibody before the allergen challenge. Eosinophilic inflammation was evaluated histologically at 24 hours after the allergen challenge. Transcriptional changes with or without a blockade of CCR3 were determined by microarray analyses.

RESULTS. Blockade of CCR3 significantly suppressed allergen-induced clinical signs, mast cell degranulation, and eosinophilic inflammation. Clustering analysis of the transcriptome during the early phase identified clusters of genes associated with distinct biological processes. A CCR2 ligand, monocyte chemoattractant protein (MCP)-1, was identified in the cluster of genes related to mast cell activation. MCP-1, an attractant of monocytes but not eosinophils, was in the top 10 transcripts among the genome and was suppressed by CCR3 blockade. Importantly, antibody blockade of MCP-1 suppressed the eosinophilic inflammation significantly.

CONCLUSIONS. CCR3 regulates not only the eosinophilic inflammation but also the clinical signs and mast cell degranulation. The CCR3-mediated transcriptome is characterized by many biological processes associated with mast cell activation. Among these CCR3-mediated processes, MCP-1 was found to be significantly involved in eosinophilic inflammation probably by an indirect pathway.

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				D. Miyazaki, T. Nakamura, M. Ohbayashi, C. H. Kuo, N. Komatsu, K. Yakura, T. Tominaga, Y. Inoue, H. Higashi, M. Murata, et al. Ablation of type I hypersensitivity in experimental allergic conjunctivitis by eotaxin-1/CCR3 blockade Int. Immunol., February 1, 2009; 21(2): 187 - 201. [Abstract] [Full Text] [PDF]