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Published on: September 18, 2016
Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C(high) CCR2(+) inflammatory
Amanda Waddell1, Richard Ahrens, Kris Steinbrecher
1Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Insights
Inflammatory monocytes expressing CCL11 drive eosinophilic inflammation in the colon during experimental colitis. Blocking monocyte recruitment reduces this inflammation, revealing a key pathway in inflammatory bowel disease.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Pediatric inflammatory bowel disease (IBD) susceptibility is linked to the 17q12 loci, containing the CCL11 gene.
- CCL11 (eotaxin-1) is an eosinophil-specific chemokine implicated in allergic inflammation.
Purpose of the Study:
- To elucidate the molecular mechanisms regulating CCL11 expression in chronic intestinal inflammation.
- To define the role of CCL11 in the pathophysiology of experimental colitis.
Main Methods:
- Utilized a murine model of dextran sodium sulfate (DSS)-induced colitis.
- Employed bone marrow chimera experiments to assess hematopoietic cell contribution.
- Analyzed inflammatory monocyte/macrophage populations (F4/80(+)CD11b(+)CCR2(+)Ly6C(high)) and their gene expression.
- Investigated the role of CCR2 in monocyte recruitment and subsequent inflammation.
Main Results:
- Hematopoietic cell-derived CCL11 is sufficient for colonic eosinophilic inflammation.
- DSS treatment increases recruitment of Ly6C(high) monocytes expressing CCL11 into the colon.
- CCR2 deficiency attenuates monocyte recruitment, decreasing CCL11 expression, eosinophilia, and colitis severity.
- Ly6C(high) intestinal macrophages exhibit a mixed M1/M2 phenotype, expressing CCL11.
Conclusions:
- Ly6C(high)CCR2(+) inflammatory monocytes/macrophages are a significant source of CCL11 in DSS-induced colitis.
- CCL11 derived from these cells mediates colonic eosinophilia and contributes to experimental colitis pathology.
- This pathway highlights a potential therapeutic target for inflammatory bowel disease.
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.
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