Department of Surgery, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
Am J Physiol Gastrointest Liver Physiol. 2011 Apr;300(4):G665-75. doi: 10.1152/ajpgi.00224.2010. Epub 2011 Feb 3.
Standardized intestinal manipulation (IM) leads to local bowel wall inflammation subsequently spreading over the entire gastrointestinal tract. Previously, we demonstrated that this so-called gastrointestinal field effect (FE) is immune mediated. This study aimed to investigate the role of CCR7 in IM-induced FE. Since CCR7 is expressed on activated dendritic cells and T cells and is well known to control their migration, we hypothesized that lack of CCR7 reduces or abolishes FE. Small bowel muscularis and colonic muscularis from CCR7(-/-) and wild-type (WT) mice were obtained after IM of the jejunum or sham operation. FE was analyzed by measuring gastrointestinal transit time of orally given fluorescent dextran (geometric center), colonic transit time, infiltration of MPO-positive cells, and circular smooth muscle contractility. Furthermore, mRNA levels of the inflammatory cytokine IL-6 were determined by RT-PCR. The number of dendritic cells and CD3+CD25+ T cells separately isolated from jejunum and colon was determined in mice after IM and sham operation. There was no significant difference in IL-6 mRNA upregulation in colonic muscularis between sham-operated WT and CCR7(-/-) mice after IM. Contractility of circular muscularis strips of the colon was significantly improved in CCR7(-/-) animals following IM and did not vary significantly from sham-operated animals. Additionally, inflammation of the colon determined by the number of MPO-positive cells and colonic transit time was significantly reduced in CCR7(-/-) mice. In contrast, jejunal contractility and jejunal inflammation of transgenic mice did not differ significantly from WT mice after IM. These data are supported by a significant increase of CD3+CD25+ T cells in the colonic muscularis of WT mice after IM, which could not be observed in CCR7(-/-) mice. These data demonstrate that CCR7 is required for FE and postoperative ileus. CCR7 indirectly affects FE by inhibiting migration of activated dendritic cells and of T cells from the jejunum to the colon. These findings support the critical role of the adaptive immune system in FE.
标准化肠道操作（IM）导致局部肠壁炎症随后扩散到整个胃肠道。此前，我们证明了这种所谓的胃肠道场效应（FE）是免疫介导的。本研究旨在探讨 CCR7 在 IM 诱导的 FE 中的作用。由于 CCR7 表达于激活的树突状细胞和 T 细胞上，并且众所周知可以控制它们的迁移，我们假设缺乏 CCR7 会减少或消除 FE。在空肠 IM 或假手术（sham operation）后，从小肠和结肠的黏膜肌层中获得 CCR7（-/-）和野生型（WT）小鼠的标本。通过测量口服给予荧光葡聚糖（几何中心）的胃肠道通过时间、结肠通过时间、MPO 阳性细胞浸润和环形平滑肌收缩性来分析 FE。此外，通过 RT-PCR 确定炎性细胞因子 IL-6 的 mRNA 水平。在 IM 和 sham 手术后，分别从空肠和结肠中分离出的树突状细胞和 CD3+CD25+T 细胞的数量。IM 后，在假手术 WT 和 CCR7（-/-）小鼠的结肠黏膜肌层中，IL-6 mRNA 的上调没有显著差异。IM 后，CCR7（-/-）动物的结肠环形肌条的收缩性明显改善，与 sham 手术动物无明显差异。另外，通过 MPO 阳性细胞数和结肠通过时间确定的结肠炎症在 CCR7（-/-）小鼠中显著减少。相反，IM 后，转基因小鼠的空肠收缩性和空肠炎症与 WT 小鼠没有显著差异。这些数据得到了以下数据的支持：在 IM 后，WT 小鼠的结肠黏膜肌层中 CD3+CD25+T 细胞的数量显著增加，而在 CCR7（-/-）小鼠中则无法观察到。这些数据表明，CCR7 是 FE 和术后肠梗阻所必需的。CCR7 通过抑制从空肠向结肠迁移的激活的树突状细胞和 T 细胞间接影响 FE。这些发现支持适应性免疫系统在 FE 中的关键作用。
