title: Membrane-bound eotaxin-3 mediates eosinophil transepithelial migration in IL-4-stimulated epithelial cells.
abstract: Epithelial cells play an important role in orchestrating mucosal immune responses. In allergic-type inflammation, epithelial cells control the recruitment of eosinophils into the mucosa. Th2-type cytokine-driven release of eosinophil-active chemokines from epithelial cells directs eosinophil migration into the mucosal epithelium. CCR3, the main eosinophil chemokine receptor, regulates this process; however, the respective contribution of individual CCR3 ligands in eosinophil transepithelial migration is less well understood. Using an in vitro transepithelial chemotaxis system, we found that eotaxin-3 produced by IL-4-stimulated airway epithelial cells and CCR3 on eosinophils exclusively mediate eosinophil transepithelial migration. Eotaxin-3 protein levels were also increased in the nasal mucosal epithelium recovered from allergic patients as compared to non-allergic patients. Surprisingly, eotaxin-3 in IL-4-stimulated airway epithelial cells was predominantly cell surface bound, and the cell surface form was critical for eosinophil transepithelial migration. Eotaxin-3 cell surface association was partially glycosaminoglycan (GAG) dependent, but was completely protein dependent, suggesting that eotaxin-3 associates with both GAG and cell surface proteins. We thus provide evidence that cell surface-associated eotaxin-3 is the critical IL-4-dependent chemotactic signal mediating eosinophil transepithelial migration in the setting of allergic inflammation.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yuan
authors.forename: Gabriele S
authors.initials: GS
authors.lastname: Campanella
authors.forename: Richard A
authors.initials: RA
authors.lastname: Colvin
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hamilos
authors.forename: Krister J
authors.initials: KJ
authors.lastname: Jones
authors.forename: Anuja
authors.initials: A
authors.lastname: Mathew
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000378:metabolism*; D009297:Nasal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: C120429:CCL26 protein, human; C515350:CCR3 protein, human; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D006025:Glycosaminoglycans; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D015847:Interleukin-4