Enhanced airway Th2 response after allergen challenge in mice deficient in CC chemokine receptor-2 (CCR2).
To evaluate the role of CCR2 in allergic asthma, mutant mice deficient in CCR2 (CCR2(-/-)) and intact mice were sensitized with i.p. OVA with alum on days 0 and 7, and challenged by inhalation with nebulization of either OVA or saline. Airway hyperreactivity, measured by the methacholine-provoked increase in enhanced pause, was significantly increased (p < 0.05) in OVA-challenged CCR2(-/-) mutant mice, compared with comparably challenged CCR2(+/+) mice. OVA-challenged CCR2(-/-) mutants also were also found to have enhanced bronchoalveolar lavage fluid eosinophilia, peribronchiolar cellular cuffing, and Ig subclass switching, with increase in OVA-specific IgG(1) and IgE. In addition, RNase protection assay revealed increased whole lung expression of IL-13 in OVA-challenged CCR2(-/-) mutants. Unexpectedly, serum monocyte chemotactic protein-1 levels were 8-fold higher in CCR2(-/-) mutants than in CCR2(+/+) mice sensitized to OVA, but OVA challenge had no additional effect on circulating monocyte chemotactic protein-1 in either genotype. Ag stimulation of lymphocytes isolated from OVA-sensitized CCR2 mutants revealed a significant increase (p < 0.05) in IL-5 production, which differed from OVA-stimulated lymphocytes from sensitized CCR2(+/+) mice. These experiments demonstrate an enhanced response in airway reactivity and in lung inflammation in CCR2(-/-) mutant mice compared with comparably sensitized and challenged CCR2(+/+) mice. These observations suggest that CC chemokines and their receptors are involved in immunomodulation of atopic asthma.
Kim
Y
Y
Division of Pulmonary and Critical Care Medicine, and Division of Rheumatology and Immunology, University of Virginia Health System, Charlottesville, VA 22908, USA.
Sung Ss
Kuziel
W A
WA
Feldman
S
S
Fu
S M
SM
Rose
C E
CE
D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D018932:Chemokine CCL2 / Q000097:blood; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007274:Injections, Intraperitoneal; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D000485:Allergens; D016085:Bronchoconstrictor Agents; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D007074:Immunoglobulin G; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D010047:Ovalbumin