Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3
Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3
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DOI：
10.1152/ajpgi.00228.2009
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发表时间：
2010-07-01
影响因子：
4.5
通讯作者：
Xavier, R. J.
中科院分区：
文献类型：
--
作者：
Beck, P. L.;Ihara, E.;Xavier, R. J.
[10]杨文，杨文，李文.通过靶向岩藻糖基转移酶VII和三叶因子3探索肠道炎症中屏障功能和白细胞募集的相互作用。美国生理学胃肠和肝脏生理学杂志299：G43-G53，2010年。首次发表于2010年3月18日; doi：10.1152/ajpgi.00228.2009。肠粘膜完整性依赖于上皮功能和对损伤的调节性免疫应答。岩藻糖基转移酶VII（Fuc-TVII）是表达E-和P-选择素的功能配体所需的必需酶。三叶因子3（TFF 3）参与保护肠上皮免受损伤以及帮助损伤后的伤口修复。本研究的目的是评估肠道炎症中屏障功能和白细胞募集之间的相互作用。更具体地说，我们旨在研究野生型或TFF 3（-/-）小鼠中Fuc-TVII的靶向破坏如何改变其对结肠损伤的易感性。通过使TFF 3（-/-）和Fuc-TVII（-/-）小鼠交配产生TFF 3和Fuc-TVII双敲除小鼠（TFF 3/Fuc-TVII（-/-）小鼠）。结肠炎是通过在饮用水中施用葡聚糖硫酸钠（DSS）（2.5%wt/vol）诱导的。每天评估基线体重、腹泻和粪便血液的变化。人道处死后，通过肉眼、显微镜和定量髓过氧化物酶（MPO）活性评估结肠炎症的程度。结肠淋巴细胞亚群在DSS给药后6天通过流式细胞术和免疫组织化学进行评估。在TFF 3/Fuc-TVII（-/-）、TFF 3（-/-）、Fuc-TVII（-/-）或野生型小鼠中未发现基线肠道炎症。Fuc-TVII的缺失导致疾病严重程度降低，而TFF 3（-/-）小鼠对DSS诱导的结肠炎明显更敏感。值得注意的是，TFF 3（-/-）小鼠中Fuc-TVII的损失显著降低了DSS诱导的结肠炎的严重程度，如减轻的体重减轻、腹泻、降低的结肠MPO水平和改善的存活所证明的。此外，TFF 3的缺失导致IL-2/β-微球蛋白缺陷小鼠中自发性结肠炎的严重程度增加。这些研究强调了参与先天免疫应答、粘膜屏障功能和参与调节白细胞募集和免疫应答其他方面的基因之间相互作用的重要性。
Beck P, Ihara E, Hirota SA, MacDonald J, Meng D, Nanthakumar N, Podolsky D, Xavier R. Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3. Am J Physiol Gastrointest Liver Physiol 299: G43-G53, 2010. First published March 18, 2010; doi:10.1152/ajpgi.00228.2009.-Intestinal mucosal integrity is dependent on epithelial function and a regulated immune response to injury. Fucosyltransferase VII (Fuc-TVII) is an essential enzyme required for the expression of the functional ligand for E- and P-selectin. Trefoil factor 3 (TFF3) is involved in both protecting the intestinal epithelium against injury as well as aiding in wound repair following injury. The aim of the present study was to assess the interplay between barrier function and leukocyte recruitment in intestinal inflammation. More specifically, we aimed to examine how targeted disruption of Fuc-TVII either in wild-type or TFF3(-/-) mice would alter their susceptibility to colonic injury. TFF3 and Fuc-TVII double-knockout mice (TFF3/Fuc-TVII(-/-) mice) were generated by mating TFF3(-/-) and Fuc-TVII(-/-) mice. Colitis was induced by administration of dextran sodium sulfate (DSS) (2.5% wt/vol) in the drinking water. Changes in baseline body weight, diarrhea, and fecal blood were assessed daily. Upon euthanasia, extents of colonic inflammation were assessed macroscopically, microscopically, and through quantification of myeloperoxidase (MPO) activity. Colonic lymphocyte subpopulations were assessed at 6 days after administration of DSS by flow cytometry and immunohistochemistry. No baseline intestinal inflammation was found in TFF3/Fuc-TVII(-/-), TFF3(-/-), Fuc-TVII(-/-), or wild-type mice. Loss of Fuc-TVII resulted in a reduction in disease severity whereas TFF3(-/-) mice were markedly more susceptible to DSS-induced colitis. Remarkably, the loss of Fuc-TVII in TFF3(-/-) mice markedly decreased the severity of DSS-induced colitis as evidenced by reduced weight loss, diarrhea, decreased colonic MPO levels and improved survival. Furthermore, the loss of TFF3 resulted in increased severity of spontaneous colitis in IL-2/beta-microglobulin-deficient mice. These studies highlight the importance of the interplay between factors involved in the innate immune response, mucosal barrier function, and genes involved in regulating leukocyte recruitment and other aspects of the immune response.