title: Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis.
abstract: Clinical studies have demonstrated a link between the eosinophil-selective chemokines, eotaxins (eotaxin-1/CCL11 and eotaxin-2/CCL24), eosinophils, and the inflammatory bowel diseases, Crohn's disease and ulcerative colitis (UC). However, the cellular source and individual contribution of the eotaxins to colonic eosinophilic accumulation in inflammatory bowel diseases remain unclear. In this study we demonstrate, by gene array and quantitative PCR, elevated levels of eotaxin-1 mRNA in the rectosigmoid colon of pediatric UC patients. We show that elevated levels of eotaxin-1 mRNA positively correlated with rectosigmoid eosinophil numbers. Further, colonic eosinophils appeared to be degranulating, and the levels positively correlated with disease severity. Using the dextran sodium sulfate (DSS)-induced intestinal epithelial injury model, we show that DSS treatment of mice strongly induced colonic eotaxin-1 and eotaxin-2 expression and eosinophil levels. Analysis of eosinophil-deficient mice defined an effector role for eosinophils in disease pathology. DSS treatment of eotaxin-2(-/-) and eotaxin-1/2(-/-) mice demonstrated that eosinophil recruitment was dependent on eotaxin-1. In situ and immunofluorescence analysis-identified eotaxin-1 expression was restricted to intestinal F4/80(+)CD11b(+) macrophages in DSS-induced epithelial injury and to CD68(+) intestinal macrophages and the basolateral compartment of intestinal epithelial cells in pediatric UC. These data demonstrate that intestinal macrophage and epithelial cell-derived eotaxin-1 plays a critical role in the regulation of eosinophil recruitment in colonic eosinophilic disease such as pediatric UC and provides a basis for targeting the eosinophil/eotaxin-1 axis in UC.
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Ahrens
authors.forename: Amanda
authors.initials: A
authors.lastname: Waddell
authors.forename: Luqman
authors.initials: L
authors.lastname: Seidu
authors.forename: Carine
authors.initials: C
authors.lastname: Blanchard
authors.forename: Rebecca
authors.initials: R
authors.lastname: Carey
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Forbes
authors.forename: Maria
authors.initials: M
authors.lastname: Lampinen
authors.forename: Tara
authors.initials: T
authors.lastname: Wilson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cohen
authors.forename: Keith
authors.initials: K
authors.lastname: Stringer
authors.forename: Edgar
authors.initials: E
authors.lastname: Ballard
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.forename: Nancy
authors.initials: N
authors.lastname: Lee
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Lee
authors.initials: L
authors.lastname: Denson
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
mesh_terms: D000293:Adolescent; D000818:Animals; D054413:Chemokine CCL11 / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000276:immunology; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054413:Chemokine CCL11; D012333:RNA, Messenger