β 7 -Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis

• Published in: Journal of hepatology 2017-06, Vol.66 (6), p.1251
• Main Authors: Drescher, Hannah K, Schippers, Angela, Clahsen, Thomas, Sahin, Hacer, Noels, Heidi, Hornef, Mathias, Wagner, Norbert, Trautwein, Christian, Streetz, Konrad L, Kroy, Daniela C
• Format: Article
• Language: English
• Subjects: Animals; Cell Adhesion Molecules - deficiency; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Choline Deficiency - complications; Diet, High-Fat - adverse effects; Disease Models, Animal; Disease Progression; Integrin beta Chains - genetics; Integrin beta Chains - metabolism; Liver - immunology; Liver - metabolism; Liver - pathology; Lymphocyte Subsets - immunology; Lymphocyte Subsets - pathology; Male; Methionine - deficiency; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Oxidative Stress
• ISSN: 1600-0641

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. It is unclear how infiltrating leukocytes affect NASH-development. Our study aims to investigate the role of the homing/receptor, pair mucosal addressin cell adhesion molecule-1 (MAdCAM-1)/β -Integrin, on immune cell recruitment and disease progression in a steatohepatitis model. Constitutive β -Integrin deficient (β ) and MAdCAM-1 deficient (MAdCAM-1 ) mice were fed a high fat diet (HFD) for 26weeks or methionine-choline-deficient-diet (MCD) for 4weeks. β mice displayed earlier and more progressive steatohepatitis during HFD- and MCD-treatment, while MAdCAM-1 mice showed less histomorphological changes. The anti-oxidative stress response was significantly weaker in β mice as reflected by a significant downregulation of the transcription factors nuclear-factor(erythroid-derived 2)-like 2 (Nrf2) and heme-oxigenase-1 (HO-1). Additionally, stronger dihydroethidium-staining revealed an increased oxidative stress response in β animals. In contrast, MAdCAM-1 mice showed an upregulation of the anti-oxidative stress response. β animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (T ) markers as well as numbers of anti-inflammatory macrophages was significantly enhanced in MAdCAM-1 mice. Those changes finally resulted in earlier and stronger collagen accumulation in β mice, whereas MAdCAM-1 mice were protected from fibrosis initiation. Adhesion molecule mediated effector cell migration contributes to the outcome of steatohepatitis in the HFD- and the MCD model. While MAdCAM-1 promotes steatohepatitis, β -Integrin unexpectedly exerts protective effects. β mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of β -Integrins and their receptor MAdCAM-1 provide novel targets for therapeutic interventions in steatohepatitis. The mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is expressed in livers upon diet-induced non-alcoholic steatohepatitis (NASH). Loss of MAdCAM-1 has beneficial effects regarding the development of NASH - manifested by reduced hepatic oxidative stress and decreased inflammation. In contrast, β -Integrin-deficiency results in increased steatohepatitis.