Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis.
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.
Ahrens
Richard
R
Division of Allergy and Immunology, Department of Pediatrics, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229, USA.
Waddell
Amanda
A
Seidu
Luqman
L
Blanchard
Carine
C
Carey
Rebecca
R
Forbes
Elizabeth
E
Lampinen
Maria
M
Wilson
Tara
T
Cohen
Elizabeth
E
Stringer
Keith
K
Ballard
Edgar
E
Munitz
Ariel
A
Xu
Huan
H
Lee
Nancy
N
Lee
James J
JJ
Rothenberg
Marc E
ME
Denson
Lee
L
Hogan
Simon P
SP
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
D054413:Chemokine CCL11; D012333:RNA, Messenger