A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation.
To clarify the role and regulation of eosinophils, we subjected several key eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in eosinophil development (Deltadbl-GATA) and eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1/2 double knockout)] were subjected to Aspergillus fumigatus-induced allergic airway inflammation. Allergen-induced eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1/2 double knockout, CCR3 knockout, and Deltadbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of eosinophil- and CCR3-deficient mice. The absence of eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was eosinophil- and CCR3-dependent; pathways downstream from eosinophils were identified, including in situ activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that eosinophils via CCR3 have a central role in chronic allergic airway disease.
Fulkerson
Patricia C
PC
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45257-0524, USA.
Fischetti
Christine A
CA
McBride
Melissa L
ML
Hassman
Lynn M
LM
Hogan
Simon P
SP
Rothenberg
Marc E
ME
D000485:Allergens / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009093:Mucus / Q000276:immunology / Q000378:metabolism; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000485:Allergens; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D020662:Guanine Nucleotide Exchange Factors; D008024:Ligands; C512843:Mcf2 protein, mouse; D054397:Receptors, CCR3; D019707:Receptors, Chemokine