BACKGROUND & AIMS

Aberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) in immune-mediated hepatitis in mice.

METHODS

Wild-type (WT) mice, MAdCAM-1-deficient mice, β7 integrin-deficient mice, RAG-2-deficient mice, RAG-2/MAdCAM-1 double-deficient mice, and RAG-2/β7 integrin double-deficient mice were subjected to concanavalin A (ConA)-induced hepatitis. The degree of hepatitis was evaluated by histology, flow cytometry, and expression analysis of inflammatory mediators. The motility of lymphocytes in progressive liver damage was assessed by intravital laser scanning multiphoton microscopy.

RESULTS

Ablation of MAdCAM-1 or β7 integrin ameliorated ConA-induced hepatitis in mice. β7 integrin-deficient lymphocytes caused less liver damage than WT lymphocytes in ConA-treated RAG-2-deficient mice. Moreover, WT lymphocytes caused less liver damage in ConA-treated RAG-2/β7 integrin double-deficient mice than in similarly treated RAG-2-deficient mice, indicating that β7 integrin expression contributes significantly to the liver damage mediated by innate immune cells. MAdCAM-1 expression was dependent on β7 integrin expression on adaptive and innate immune cells. Most importantly, lymphocytes in ConA-treated MAdCAM-1-deficient mice displayed more motility and less adhesion in the liver sinusoids in vivo, than lymphocytes in similarly treated WT mice.

CONCLUSIONS

These data suggest that β7 integrin expression on lymphocytes and innate immune cells contributes to MAdCAM-1 upregulation and liver damage in acute immune-mediated hepatitis, most likely by facilitating lymphocyte/sinusoidal endothelial cell interactions.

中文翻译：

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MAdCAM-1/α4β7 整合素介导的淋巴细胞/内皮相互作用加剧了小鼠急性免疫介导的肝炎

背景与目标

异常的淋巴细胞归巢可能将肠道和肝脏中的炎症过程联系起来，因为不同的肝胆疾病经常发展为炎症性肠病的肠外表现。在这项研究中，我们检查了肠道嗜性白细胞粘附分子 β7 整合素及其内皮配体粘膜寻址素细胞粘附分子 1 (MAdCAM-1) 在小鼠免疫介导的肝炎中的作用。

方法

野生型 (WT) 小鼠、MAdCAM-1 缺陷型小鼠、β7 整合素缺陷型小鼠、RAG-2 缺陷型小鼠、RAG-2/MAdCAM-1 双缺陷型小鼠和 RAG-2/β7 整合素双缺陷型小鼠小鼠遭受伴刀豆球蛋白 A (ConA) 诱发的肝炎。通过组织学、流式细胞术和炎症介质的表达分析评估肝炎的程度。通过活体激光扫描多光子显微镜评估进行性肝损伤中淋巴细胞的运动性。

结果

MAdCAM-1 或 β7 整合素的消融改善了 ConA 诱导的小鼠肝炎。在 ConA 处理的 RAG-2 缺陷小鼠中，β7 整合素缺陷淋巴细胞比 WT 淋巴细胞引起的肝损伤更小。此外，与类似处理的 RAG-2 缺陷小鼠相比，WT 淋巴细胞在经 ConA 处理的 RAG-2/β7 整合素双缺陷小鼠中引起的肝损伤较少，表明 β7 整合素表达对先天免疫细胞介导的肝损伤有显着贡献。MAdCAM-1 表达依赖于适应性和先天免疫细胞上 β7 整合素的表达。最重要的是，与同样处理的 WT 小鼠中的淋巴细胞相比，ConA 处理的 MAdCAM-1 缺陷小鼠中的淋巴细胞在体内表现出更多的运动性和更少的粘附在肝窦中。

结论

这些数据表明，淋巴细胞和先天免疫细胞上的 β7 整合素表达有助于急性免疫介导的肝炎中的 MAdCAM-1 上调和肝损伤，很可能是通过促进淋巴细胞/血窦内皮细胞相互作用。