title: Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C(high) CCR2(+) inflammatory monocyte/macrophage-derived CCL11.
abstract: Recent genome-wide association studies of pediatric inflammatory bowel disease have implicated the 17q12 loci, which contains the eosinophil-specific chemokine gene CCL11, with early-onset inflammatory bowel disease susceptibility. In the current study, we employed a murine model of experimental colitis to define the molecular pathways that regulate CCL11 expression in the chronic intestinal inflammation and pathophysiology of experimental colitis. Bone marrow chimera experiments showed that hematopoietic cell-derived CCL11 is sufficient for CCL11-mediated colonic eosinophilic inflammation. We show that dextran sodium sulfate (DSS) treatment promotes the recruitment of F4/80(+)CD11b(+)CCR2(+)Ly6C(high) inflammatory monocytes into the colon. F4/80(+)CD11b(+)CCR2(+)Ly6C(high) monocytes express CCL11, and their recruitment positively correlated with colonic eosinophilic inflammation. Phenotypic analysis of purified Ly6C(high) intestinal inflammatory macrophages revealed that these cells express both M1- and M2-associated genes, including Il6, Ccl4, Cxcl2, Arg1, Chi3l3, Ccl11, and Il10, respectively. Attenuation of DSS-induced F4/80(+)CD11b(+)CCR2(+)Ly6C(high) monocyte recruitment to the colon in CCR2(-/-) mice was associated with decreased colonic CCL11 expression, eosinophilic inflammation, and DSS-induced histopathology. These studies identify a mechanism for DSS-induced colonic eosinophilia mediated by Ly6C(high)CCR2(+) inflammatory monocyte/macrophage-derived CCL11.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Waddell
authors.forename: Richard
authors.initials: R
authors.lastname: Ahrens
authors.forename: Kris
authors.initials: K
authors.lastname: Steinbrecher
authors.forename: Burke
authors.initials: B
authors.lastname: Donovan
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D000950:Antigens, Ly / Q000032:analysis / Q000276:immunology; D001854:Bone Marrow Cells; D039481:CD11b Antigen / Q000276:immunology; D054413:Chemokine CCL11 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D003106:Colon / Q000276:immunology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004802:Eosinophilia / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D016133:Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000032:analysis / Q000276:immunology
chemical_list: D000943:Antigens, Differentiation; D000950:Antigens, Ly; D039481:CD11b Antigen; C515457:Ccl11 protein, mouse; C515335:Ccr2 protein, mouse; D054413:Chemokine CCL11; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; C036763:monocyte-macrophage differentiation antigen; D016264:Dextran Sulfate