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Originally published In Press as doi:10.1167/iovs.09-3637 on June 24, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:5181-5188.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3637
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Blocking Mast Cell–Mediated Type I Hypersensitivity in Experimental Allergic Conjunctivitis by Monocyte Chemoattractant Protein-1/CCR2

Takeshi Tominaga, Dai Miyazaki, Shin-ichi Sasaki, Sachiko Mihara, Naoki Komatsu, Keiko Yakura, and Yoshitsugu Inoue

From the Division of Ophthalmology and Visual Science, Tottori University Faculty of Medicine, Tottori, Japan.

Corresponding author: Dai Miyazaki, Division of Ophthalmology and Visual Science, Tottori University Faculty of Medicine, 36-1 Nishicho, Yonago Tottori 683-8504, Japan; dm{at}grape.med.tottori-u.ac.jp.

Purpose. To characterize the roles played by monocyte chemoattractant protein-1 and its preferential receptor CCR2 (MCP-1/CCL2) in acute allergic inflammation.

Methods. The direct effects of MCP-1 were evaluated histologically after a subconjunctival injection of recombinant MCP-1 into naïve mice. The mice were sensitized to ragweed pollen, and allergic conjunctivitis was induced by an allergen challenge. The location of the induced MCP-1 was determined by immunohistochemistry. Anti-MCP-1 antibody and CCR2-specific antagonist, RS 504393, were used to determine whether an inhibition of MCP-1 or CCR2 signals would suppress the allergen-induced immediate hypersensitivity reaction. The effect of blocking CCR2 was tested in vitro with isolated mast cells from connective tissue, to evaluate the co-stimulatory signals mediated by CCR2 in mast cells directly.

Results. A subconjunctival injection of MCP-1 stimulated conjunctival mast cell degranulation and recruited monocytes/macrophages. In the allergic conjunctivitis model, the allergen-induced MCP-1 protein was located in the monocytes/macrophages in the substantia propria of the conjunctiva. Blocking MCP-1 significantly suppressed the allergen-induced clinical signs and mast cell degranulation without affecting the allergen-specific IgE, or the release of Th2 cytokine from the isolated draining lymph node cells. Inhibition of CCR2 similarly suppressed the acute inflammatory responses. Consistent with the outcome of the disease model, inhibition of CCR2 suppressed allergen-specific degranulation of IgE-primed, isolated conjunctival mast cells.

Conclusions. Stimulation of the co-stimulatory axis of CCR2 by MCP-1 is essentially required for mast cell–mediated hypersensitivity reactions in mouse eyes.






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