ß7-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis.

ABSTRACT

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)/ß7-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model. METHODS: Constitutive ß7-Integrin deficient (ß7-/-) and MAdCAM-1 deficient (MAdCAM-1-/-) mice were fed a high fat diet (HFD) for 26weeks or methionine-choline-deficient-diet (MCD) for 4weeks. RESULTS: ß7-/- 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 ß7-/- 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 ß7-/- animals. In contrast, MAdCAM-1-/- mice showed an upregulation of the anti-oxidative stress response. ß7-/- animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (TReg) 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 ß7-/- 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, ß7-Integrin unexpectedly exerts protective effects. ß7-/- mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of ß7-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 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, ß7-Integrin-deficiency results in increased steatohepatitis.