| First Author | Schippers A | Year | 2021 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 11 |
| Issue | 4 | Pages | 1227-1250.e1 |
| PubMed ID | 33316453 | Mgi Jnum | J:336647 |
| Mgi Id | MGI:6809727 | Doi | 10.1016/j.jcmgh.2020.12.003 |
| Citation | Schippers A, et al. (2021) MAdCAM-1/alpha4beta7 Integrin-Mediated Lymphocyte/Endothelium Interactions Exacerbate Acute Immune-Mediated Hepatitis in Mice. Cell Mol Gastroenterol Hepatol 11(4):1227-1250.e1 |
| abstractText | 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 beta7 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, beta7 integrin-deficient mice, RAG-2-deficient mice, RAG-2/MAdCAM-1 double-deficient mice, and RAG-2/beta7 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 beta7 integrin ameliorated ConA-induced hepatitis in mice. beta7 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/beta7 integrin double-deficient mice than in similarly treated RAG-2-deficient mice, indicating that beta7 integrin expression contributes significantly to the liver damage mediated by innate immune cells. MAdCAM-1 expression was dependent on beta7 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 beta7 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. |
