Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis.
Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis.
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DOI：
10.4049/jimmunol.181.10.7390
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发表时间：
2008-11-15
期刊：
影响因子：
--
通讯作者：
Hogan SP
中科院分区：
文献类型：
--
作者：
Ahrens R;Waddell A;Seidu L;Blanchard C;Carey R;Forbes E;Lampinen M;Wilson T;Cohen E;Stringer K;Ballard E;Munitz A;Xu H;Lee N;Lee JJ;Rothenberg ME;Denson L;Hogan SP
临床研究已经证明嗜酸性粒细胞选择性趋化因子、嗜酸性粒细胞趋化因子（eotaxin-1/CCL 11和eotaxin-2/CCL 24）、嗜酸性粒细胞与炎症性肠病、克罗恩病和溃疡性结肠炎（UC）之间的联系。然而，在炎症性肠病中，嗜酸性粒细胞趋化因子对结肠嗜酸性粒细胞积聚的细胞来源和个体贡献仍不清楚。在这项研究中，我们证明，通过基因阵列和定量PCR，在儿童UC患者的直肠乙状结肠Eotaxin-1 mRNA的水平升高。我们发现，Eotaxin-1 mRNA水平升高与直肠乙状结肠嗜酸性粒细胞数量呈正相关。此外，结肠嗜酸性粒细胞似乎正在脱粒，并且水平与疾病严重程度正相关。使用葡聚糖硫酸钠（DSS）诱导的肠上皮损伤模型，我们表明DSS治疗小鼠强烈诱导结肠嗜酸性粒细胞活化趋化因子-1和嗜酸性粒细胞活化趋化因子-2表达和嗜酸性粒细胞水平。对嗜酸性粒细胞缺陷小鼠的分析确定了嗜酸性粒细胞在疾病病理学中的效应作用。DSS处理的嗜酸性粒细胞趋化因子-2-/-和嗜酸性粒细胞趋化因子-1/2-/-小鼠表明，嗜酸性粒细胞募集依赖于嗜酸性粒细胞趋化因子-1。原位和免疫荧光分析鉴定的eotaxin-1表达仅限于DSS诱导的上皮损伤中的肠F4/80+ CD 11b+巨噬细胞和儿科UC中的CD 68+肠巨噬细胞和肠上皮细胞的基底外侧隔室。这些数据表明，肠巨噬细胞和上皮细胞来源的嗜酸性粒细胞活化趋化因子-1在结肠嗜酸性粒细胞疾病（如小儿UC）中调节嗜酸性粒细胞募集中起关键作用，并为靶向UC中的嗜酸性粒细胞/嗜酸性粒细胞活化趋化因子-1轴提供了基础。
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.
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