The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 3, 1479-1484, February 5, 2002
Alison A. Humbles*, Bao Lu*, Daniel S. Friend+, Shoji Okinaga*, Jose Lora~, Amal Al-garawi~, Thomas R. Martin§, Norma P. Gerard*, and Craig Gerard*
* Ina Sue Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, MA 02115;+ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;~ Department of Biology, Inflammation Division, Millennium Pharmaceuticals Incorporated, 45-75 Sidney Street, Cambridge, MA 02139; and § Tufts, New England Medical Centre, Boston, MA 02111
CCR3 is a chemokine receptor initially thought specific to eosinophils but subsequently identified on TH2 cell subsets, basophils, mast cells, neural tissue, and some epithelia. Because of the prominent role of these cells in allergic disease, including asthma, we generated mice deficient in CCR3 to determine its contribution in a model of allergic airway disease. Here we show that CCR3 is important for the basal trafficking of eosinophils to the intestinal mucosa but not the lung. In contrast, CCR3 disruption significantly curtails eosinophil recruitment to the lung after allergen challenge, with the majority of the eosinophils being arrested in the subendothelial space. Further, a role for CCR3 in mast cell homing has been identified; after sensitization and allergen challenge, we find increased numbers of intraepithelial mast cells in the trachea of knockout mice. Physiologically, we find that the net result of these complex cell fates after sensitization and allergen challenge is a paradoxical increase in airway responsiveness to cholinergic stimulation. These data underscore a more complex role for CCR3 in allergic disease than was anticipated.
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www.pnas.org/cgi/doi/10.1073/pnas.261462598 |
