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Waddell, A. et al. Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C(high) CCR2(+) inflammatory monocyte/macrophage-derived CCL11. J. Immunol. 186, 5993-6003

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
The Journal of Immunology (Impact Factor: 5.36). 05/2011; 186(10):5993-6003. DOI: 10.4049/jimmunol.1003844
Source: PubMed

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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    • "Ly6Chi monocytes are characterized by high expression of the chemokine receptor CCR2, adhesion molecule CD62L and low expression of the fractalkine receptor CX3CR1[48,51,58]. These cells have been termed ‘inflammatory’ because they are selectively recruited to sites of inflammation and infection in many models of disease, including atherosclerosis [59-62]; rheumatoid arthritis [63]; experimental colitis [64]; cardiac infarction [65]; and CNS infections including experimental autoimmune encephalomyelitis (EAE) [66,67], amyotrophic lateral sclerosis [68], and stroke [53]. Recent studies have shown that these cells are also recruited to the virus-infected brain in animal models of HSV, HIV, murine hepatitis virus (MHV), Theiler’s murine encephalomyelitis virus (TMEV) and a number of flaviviral encephalitides, where they give rise to macrophage, DC and, arguably, to microglial populations [11,13,14,69]. "
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    • "Monocyte Descendants in the Inflamed Colon accordance with earlier reports on other colitis models (Rivollier et al., 2012; Weber et al., 2011) or DSS-induced colitis (Platt et al., 2010; Waddell et al., 2011), flow cytometry analysis of the inflamed colonic lamina propria revealed the progressive emergence of CX 3 CR1-GFP int cells concomitant with a marked reduction in the frequency of CX 3 CR1-GFP hi resident macrophages (Figure 2A). The accumulation of CX 3 CR1-GFP int cells reached its peak at day 7 after the initial DSS exposure, outnumbering CX 3 CR1-GFP hi resident macrophages by 10-fold, and was associated with neutrophil infiltration and significant destruction of the crypt architecture, as determined by histology (Figures 2A– 2C). "
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