Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6Chigh CCR2+ inflammatory monocyte/macrophage-derived CCL11

Amanda Waddell, Richard Ahrens, Kris Steinbrecher, Burke Donovan, Marc E. Rothenberg, Ariel Munitz, Simon P. Hogan

Research output: Contribution to journalArticlepeer-review

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+Ly6Chigh inflammatory monocytes into the colon. F4/80+ CD11b+CCR2 +Ly6Chigh monocytes express CCL11, and their recruitment positively correlated with colonic eosinophilic inflammation. Phenotypic analysis of purified Ly6Chigh 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+Ly6Chigh 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 Ly6ChighCCR2+ inflammatory monocyte/macrophage-derived CCL11.

Original languageEnglish
Pages (from-to)5993-6003
Number of pages11
JournalJournal of Immunology
Volume186
Issue number10
DOIs
StatePublished - 15 May 2011

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