Enhanced pulmonary allergic responses to Aspergillus in CCR2-/- mice.
Allergic responses to Aspergillus species exacerbate asthma and cystic fibrosis. The natural defense against live Aspergillus fumigatus spores or conidia depends on the recruitment and activation of mononuclear and polymorphonuclear leukocytes, events that are dependent on chemotactic cytokines. In this study, we explored the relative contribution of the monocyte chemoattractant protein-1 receptor, CCR2, in the pulmonary response to A. fumigatus conidia. Following sensitization to soluble A. fumigatus Ags, mice lacking CCR2 due to targeted deletion were markedly more susceptible to the injurious effects of an intrapulmonary challenge with live conidia compared with mice that expressed CCR2 or CCR2+/+. CCR2-/- mice exhibited a major defect in the recruitment of polymorphonuclear cells, but these mice also had significantly more eosinophils and lymphocytes in bronchoalveolar lavage samples. CCR2-/- mice also had significant increases in serum levels of total IgE and whole lung levels of IL-5, IL-13, eotaxin, and RANTES compared with CCR2+/+ mice. Airway inflammation, hyper-responsiveness to spasmogens, and subepithelial fibrosis were significantly enhanced in CCR2-/- mice compared with CCR2+/+ mice after the conidia challenge. Thus, these findings demonstrate that CCR2 plays an important role in the immune response against A. fumigatus, thereby limiting the allergic airway inflammatory and remodeling responses to this fungus.
Blease
K
K
Department of Pathology, Division of Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Mehrad
B
B
Standiford
T J
TJ
Lukacs
N W
NW
Gosling
J
J
Boring
L
L
Charo
I F
IF
Kunkel
S L
SL
Hogaboam
C M
CM
D000818:Animals; D000946:Antigens, Fungal / Q000008:administration & dosage / Q000276:immunology; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000819:agonists; D054422:Chemokine CCL22; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054410:Chemokine CCL7; D019742:Chemokines, CC / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D005355:Fibrosis; D016867:Immunocompromised Host / Q000235:genetics; D007073:Immunoglobulin E / Q000097:blood; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D018793:Interleukin-13 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000819:agonists; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000819:agonists / Q000172:deficiency* / Q000235:genetics*; D013172:Spores, Fungal / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013997:Time Factors
D000946:Antigens, Fungal; C515457:Ccl11 protein, mouse; C515483:Ccl22 protein, mouse; C515451:Ccl7 protein, mouse; C515335:Ccr2 protein, mouse; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D054422:Chemokine CCL22; D018946:Chemokine CCL5; D054410:Chemokine CCL7; D019742:Chemokines, CC; D016207:Cytokines; D018793:Interleukin-13; D015848:Interleukin-5; D018945:Monocyte Chemoattractant Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D007073:Immunoglobulin E