β7-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis

Background & Aims: 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)/beta(7)-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model. Methods: Constitutive beta(7)-Integrin deficient (beta(-/-)(7)) and MAdCAM-1 deficient (MAdCAM-1(-/-)) mice were fed a high fat diet (HFD) for 26 weeks or methionine-choline-deficient-diet (MCD) for 4 weeks. Results: beta(-/-)(7) 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 beta(-/-)(7) 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 beta(-/-)(7) animals. In contrast, MAdCAM-1(-/-) mice showed an upregulation of the anti-oxidative stress response. beta(-/-)(7) animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (T-Reg) 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 beta(-/-)(7) mice, whereas MAdCAM-1(-/-) mice were protected from fibrosis initiation. Conclusions: Adhesion molecule mediated effector cell migration contributes to the outcome of steatohepatitis in the HFD and the MCD model. While MAdCAM-1 promotes steatohepatitis, beta(7)-Integrin unexpectedly exerts protective effects. beta(-/-)(7) mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of beta(7)-Integrins and their receptor MAdCAM-1 provide novel targets for therapeutic interventions in steatohepatitis. Lay summary: The mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is expressed in livers upon diet-induced nonalcoholic 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, beta(7)-Integrin-deficiency results in increased steatohepatitis. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.