A Central Regulatory Role for Eosinophils and the Eotaxin/CCR3 Axis in Chronic Experimental Allergic Airway Inflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-10, Vol.103 (44), p.16418-16423
• Main Authors: Fulkerson, Patricia C., Fischetti, Christine A., McBride, Melissa L., Hassman, Lynn M., Hogan, Simon P., Rothenberg, Marc E.
• Format: Article
• Language: English
• Subjects: Airway management; Allergens; Allergens - immunology; Allergies; Animals; Asthma; Biological Sciences; Bronchial Hyperreactivity - genetics; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - metabolism; Bronchial Hyperreactivity - pathology; Cell Movement; Chemokine CCL11; Chemokines, CC - deficiency; Chemokines, CC - genetics; Chemokines, CC - immunology; Chemokines, CC - metabolism; Chronic Disease; Cytokines; Cytokines - biosynthesis; Disease Models, Animal; Eosinophils; Eosinophils - cytology; Eosinophils - immunology; Eosinophils - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Guanine Nucleotide Exchange Factors - deficiency; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Inflammation - pathology; Leukocytes; Ligands; Lungs; Lymphocytes; Mast Cells - metabolism; Mice; Mice, Knockout; Mucus - immunology; Mucus - metabolism; Neutrophils; Receptors, CCR3; Receptors, Chemokine - deficiency; Receptors, Chemokine - genetics; Receptors, Chemokine - immunology; Receptors, Chemokine - metabolism; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0607863103

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 (ΔdblGATA) 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 Δdbl-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.