Role of β7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF-dependent Crohn's disease
Role of β7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF-dependent Crohn's disease
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DOI：
10.1053/j.gastro.2008.02.085
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发表时间：
2008-06-01
期刊：
影响因子：
29.4
通讯作者：
Kollias, George
中科院分区：
文献类型：
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作者：
Apostolaki, Maria;Manoloukos, Menelaos;Kollias, George
背景和目标：在目前的工作中，我们解决了在克罗恩病样炎症性肠病的CD 8（+）T细胞依赖性Tnf（Δ ARE）小鼠模型的发病机制中对趋化因子/趋化因子受体对CCL 25/CCR 9和β 7整联蛋白的尿特异性归巢分子的需求。研究方法：我们通过流式细胞术研究了肠上皮和固有层（LP）中淋巴细胞的募集;上皮内和LP淋巴细胞的细胞因子产生;以及CCR 9、α 4 β 7和α E β 7整联蛋白的外周表达。在遗传上缺乏这些分子的Tnf（Δ ARE）小鼠中评估了CCL 25/CCR 9和β 7整联蛋白在炎性淋巴细胞募集和肠道疾病发展中的功能意义。结果如下：TNF中的肠道炎症（Δ ARE）小鼠与表达CD 8 α α的上皮内淋巴细胞的早期减少、LP CD 4（+）淋巴细胞对T辅助细胞1的减少和T辅助细胞17的增加的应答、外周活化/记忆细胞归巢CD 8 α β淋巴细胞中α E β 7整联蛋白表达的增加、以及上皮中肿瘤坏死因子/干扰素-γ-产生的CD 8 α β淋巴细胞占优势。尽管CCL 25/CCR 9与T淋巴细胞向小肠的募集密切相关，但炎症病理学在CCL 25/CCR 9的遗传缺失下不受干扰地发展。此外，在CCR 9或CCL 25缺陷型Tnf（Δ ARE）小鼠中，肠上皮中的CD 8 α β淋巴细胞募集和LP中的炎性浸润未受损。相比之下，β 7整联蛋白的基因消除导致肠道病理学的完全改善。结论：我们的研究结果表明，Tnf（Δ ARE）小鼠肠道炎症的发展严重依赖于β 7整合素介导的T淋巴细胞募集，而在该模型中，CCL 25/CCR 9轴的功能似乎不稳定。
Background & Aims: In the present work, we address the requirement for intestinal-specific homing molecules, the chemokine/chemokine receptor pair CCL25/CCR9 and beta 7 integrin, in the pathogenesis of the CD8(+) T cell-dependent Tnf(Delta ARE) mouse model of Crohn's-like inflammatory bowel disease. Methods: We investigated by flow cytometry lymphocyte recruitment in the intestinal epithelium and lamina propria (LP); cytokine production by intraepithelial and LP lymphocytes; and peripheral expression of CCR9, alpha 4 beta 7, and alpha E beta 7 integrin. The functional significance of CCL25/CCR9 and beta 7 integrin in inflammatory lymphocyte recruitment and intestinal disease development was assessed in Tnf(Delta ARE) mice genetically lacking these molecules. Results: Intestinal inflammation in the Tnf(Delta ARE) mice is associated with early reduction of CD8 alpha alpha-expressing intraepithelial lymphocytes, decreased T helper cell 1 and increased T helper cell 17 responses by LP CD4(+) lymphocytes, increased alpha E beta 7 integrin expression in peripheral activated/memory intestinal-homing CD8 alpha beta lymphocytes, and predominance of tumor necrosis factor/interferon-gamma-producing CD8 alpha beta lymphocytes in the epithelium. Although CCL25/CCR9 have been strongly implicated in T-lymphocyte recruitment to the small intestine, inflammatory pathology develops unperturbed in the genetic absence of CCL25/CCR9. Furthermore, CD8 alpha beta lymphocyte recruitment in the intestinal epithelium and inflammatory infiltration in the LP are not impaired in CCR9- or CCL25-deficient Tnf(Delta ARE) mice. In contrast, genetic ablation of beta 7 integrin results in complete amelioration of intestinal pathology. Conclusions: Our findings demonstrate that development of intestinal inflammation in the Tnf(Delta ARE) mice is critically dependent on beta 7 integrin-mediated T-lymphocyte recruitment, whereas the function of the CCL25/CCR9 axis appears dispensable in this model.