CD44 Deficiency Attenuates Chronic Murine Ileitis
CD44 Deficiency Attenuates Chronic Murine Ileitis
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DOI：
10.1053/j.gastro.2008.08.053
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发表时间：
2008-12-01
期刊：
影响因子：
29.4
通讯作者：
Rivera-Nieves, Jesus
中科院分区：
文献类型：
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作者：
Collins, Colm B.;Ho, Johnson;Rivera-Nieves, Jesus
背景与目的：淋巴细胞募集到炎症部位需要粘附分子和趋化因子受体的连续参与。在目前的研究中，我们分析了CD44在体内慢性小肠炎症浸润发展中的作用。方法：利用肿瘤坏死因子（TNF）驱动的慢性回肠炎模型(即B6.129P-TNF - δ AU-rich (element) ([ARE]))，通过酶联免疫吸附法、实时逆转录聚合酶链反应、免疫组织化学和流式细胞术观察CD44及其配体透明质酸的表达和功能状态的动态变化。此外，我们通过过继转移研究评估了淋巴细胞群在诱导回肠炎中的作用，并生成了CD44缺失的TNF δ ARE小鼠来评估CD44在回肠炎发展中的作用。结果：TNF δ ARE小鼠的可溶性透明质酸水平和透明质酸合成酶-1的表达均升高。这与CD4(+) T细胞上CD44（包括变体7）的表达增加和对透明质酸的反应性增加相吻合。CD44在空间上与肠归巢整合素共定位(4)，在空间上连接淋巴细胞滚动与阻滞。这些细胞具有效应表型，因为它们缺乏l -选择素，与野生型幼崽相比，患病小鼠中产生TNF和白细胞介素-2的比例更高。最后，CD4(+) T细胞而不是CD8(+) T细胞将回肠炎赋予RAG（-/-）受体，缺乏CD44基因的一个或两个等位基因导致TNF - δ ARE小鼠回肠炎的严重程度减轻。结论：我们的研究结果支持CD4（+）和CD8（+）表达的CD44在TNF过量产生介导的回肠炎发展中的重要作用。
Background & Aims: Lymphocyte recruitment to sites of inflammation requires the sequential engagement of adhesion molecules and chemokine receptors. In the current studies we analyzed the role of CD44 for the development of chronic small-intestinal inflammatory infiltrates in vivo. Methods: By using a tumor necrosis factor (TNF)-driven model of chronic ileitis (ie, B6.129P-TNF Delta AU-rich (element) ([ARE])) that recapitulates many features of Crohn's disease, we noticed dynamic changes in the expression and functional state of CD44 and its ligand hyaluronan via enzyme-linked immunosorbent assay, real-time reverse-transcription polymerase chain reaction, immunohistochemistry, and flow cytometry. In addition, we assessed the role of lymphocyte populations during induction of ileitis through adoptive transfer studies, and generated CD44-deficient TNF Delta ARE mice to assess the role of CD44 for development of ileitis. Results: Soluble hyaluronan levels and expression of hyaluronan synthase-1 were increased in TNF Delta ARE mice. This coincided with increased expression of CD44 (including variant 7) and reactivity towards hyaluronan on CD4(+) T cells. CD44 was spatially co-localized with the gut-homing integrin alpha(4)beta(7), spatially linking lymphocyte rolling with arrest. These cells had an effector phenotype because they lacked L-selectin and a higher proportion in diseased mice produced TNF and interleukin-2 compared with wild-type littermates. Lastly, CD4(+) but not CD8(+) T cells conferred ileitis to RAG(-/-) recipients and deficiency of one or both alleles of the CD44 gene resulted in attenuation of the severity of ileitis in TNF Delta ARE mice. Conclusions: Our findings support an important role of CD44 expressed by CD4(+) and CD8(+) for development of ileitis mediated by TNF overproduction.