Blocking mast cell-mediated type I hypersensitivity in experimental allergic conjunctivitis by monocyte chemoattractant protein-1/CCR2.
OBJECTIVE
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.
Tominaga
Takeshi
T
Division of Ophthalmology and Visual Science, Tottori University Faculty of Medicine, Tottori, Japan.
Miyazaki
Dai
D
Sasaki
Shin-ichi
S
Mihara
Sachiko
S
Komatsu
Naoki
N
Yakura
Keiko
K
Inoue
Yoshitsugu
Y
D000485:Allergens / Q000633:toxicity; D000818:Animals; D015550:Cell Degranulation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D003228:Conjunctiva / Q000187:drug effects; D003233:Conjunctivitis, Allergic / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000502:physiology; D019084:Fluorescent Antibody Technique, Indirect; D007073:Immunoglobulin E / Q000276:immunology; D008264:Macrophages / Q000502:physiology; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000502:physiology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology
D000485:Allergens; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D054390:Receptors, CCR2; D011994:Recombinant Proteins; D007073:Immunoglobulin E