The eotaxin chemokines and CCR3 are fundamental regulators of allergen-induced pulmonary eosinophilia.
The eotaxin chemokines have been implicated in allergen-induced eosinophil responses in the lung. However, the individual and combined contribution of each of the individual eotaxins is not well defined. We aimed to examine the consequences of genetically ablating eotaxin-1 or eotaxin-2 alone, eotaxin-1 and eotaxin-2 together, and CCR3. Mice carrying targeted deletions of these individual or combined genes were subjected to an OVA-induced experimental asthma model. Analysis of airway (luminal) eosinophilia revealed a dominant role for eotaxin-2 and a synergistic reduction in eotaxin-1/2 double-deficient (DKO) and CCR3-deficient mice. Examination of pulmonary tissue eosinophilia revealed a modest role for individually ablated eotaxin-1 or eotaxin-2. However, eotaxin-1/2 DKO mice had a marked decrease in tissue eosinophilia approaching the low levels seen in CCR3-deficient mice. Notably, the organized accumulation of eosinophils in the peribronchial and perivascular regions of allergen-challenged wild-type mice was lost in eotaxin-1/2 DKO and CCR3-deficient mice. Mechanistic analysis revealed distinct expression of eotaxin-2 in bronchoalveolar lavage fluid cells consistent with macrophages. Taken together, these results provide definitive evidence for a fundamental role of the eotaxin/CCR3 pathway in eosinophil recruitment in experimental asthma. These results imply that successful blockade of Ag-induced pulmonary eosinophilia will require antagonism of multiple CCR3 ligands.
Pope
Samuel M
SM
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Zimmermann
Nives
N
Stringer
Keith F
KF
Karow
Margaret L
ML
Rothenberg
Marc E
ME
D000485:Allergens / Q000276:immunology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D019742:Chemokines, CC / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000485:Allergens; C515457:Ccl11 protein, mouse; C515485:Ccl24 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D019742:Chemokines, CC; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D010047:Ovalbumin