MAdCAM-1/α4β7 Integrin-Mediated Lymphocyte/Endothelium Interactions Exacerbate Acute Immune-Mediated Hepatitis in Mice
| Autor: | Klaus Tenbrock, Jessica Hübel, Angela Schippers, Sreepradha Eswaran, Sarah Schlepütz, Nikolaus Gaßler, Felix Heymann, Thomas Clahsen, Robin Püllen, Frank Tacke, Norbert Wagner |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Integrins Lymphocyte PAI plasminogen activator inhibitor-1 ConA concanavalin A RT-PCR real-time polymerase chain reaction VCAM-1 vascular cell adhesion molecule-1 Hepatitis Mice 0302 clinical medicine DC dendritic cell Mucoproteins Concanavalin A Medicine Lymphocytes Original Research Mice Knockout biology IBD inflammatory bowel disease Cell adhesion molecule Gastroenterology mRNA messenger RNA DNA-Binding Proteins medicine.anatomical_structure 030211 gastroenterology & hepatology NK natural killer Adhesion Molecules Leukocyte adhesion molecule PBS phosphate-buffered saline Cell Migration TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling 03 medical and health sciences Immune system Addressin Animals ddc:610 lcsh:RC799-869 Lymphocyte homing receptor KC Kupffer cells Innate immune system Hepatology business.industry medicine.disease TSA tyramide signal amplification WT wild-type Mice Inbred C57BL 030104 developmental biology MAdCAM-1 mucosal addressin cell-adhesion molecule-1 TF tissue factor Cancer research biology.protein H&E hematoxylin and eosin lcsh:Diseases of the digestive system. Gastroenterology BSA bovine serum albumin Endothelium Vascular Mitogens business Cell Adhesion Molecules |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology : CMGH 11(4), 1227-1250.el (2021). doi:10.1016/j.jcmgh.2020.12.003 Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 4, Pp 1227-1250.e1 (2021) |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2020.12.003 |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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