Eosinophils and CCR3 regulate interleukin-13 transgene-induced pulmonary remodeling.
Interleukin (IL)-13 transgene overexpression in the lung induces features of chronic inflammatory lung disorders, including an eosinophil-rich inflammatory cell infiltration, airway hyper-reactivity, and remodeling of the airway (eg, subepithelial fibrosis, goblet cell metaplasia, and smooth muscle hypertrophy and hyperplasia). Here, we aimed to define the role of eosinophils and eosinophil signaling molecules [eg, eotaxins and CC chemokine receptor (CCR) 3] in IL-13-mediated airway disease. To accomplish this, we mated IL-13-inducible lung transgenic mice with mice deficient in eosinophil chemoattractant molecules (eotaxin-1, eotaxin-2, and their receptor CCR3) and with mice genetically deficient in eosinophils (Deltadbl-GATA). We report that in the absence of eotaxin-2 or CCR3, there was a profound reduction in IL-13-induced eosinophil recruitment into the lung lumen. In contrast, in the absence of eotaxin-1, there was a fourfold increase in IL-13-mediated eosinophil recruitment into the airway. IL-13 transgenic mice deficient in CCR3 had a 98% reduction in lung eosinophils. Furthermore, the reduction in pulmonary eosinophils correlated with attenuation in IL-13-induced mucus cell metaplasia and collagen deposition. Mechanistic analysis identified alterations in pulmonary protease and transforming growth factor-beta1 expression in eosinophil-deficient mice. Taken together, these data definitively identify a functional contribution by eosinophils on the effects of chronic IL-13 expression in the lung.
Fulkerson
Patricia C
PC
Deparmtnet of Molecular Genetics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., MLC 7028, Cincinnati, OH 45229, USA.
Fischetti
Christine A
CA
Rothenberg
Marc E
ME
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004804:Eosinophils / Q000502:physiology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009093:Mucus / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000378:metabolism* / Q000502:physiology
C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D018793:Interleukin-13; D008024:Ligands; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D003094:Collagen; D010447:Peptide Hydrolases