β7-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)/β₇-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model.

Methods: Constitutive β₇-Integrin deficient (β₇^-/-) 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: β₇^-/- 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 β₇^-/- 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 β₇^-/- animals. In contrast, MAdCAM-1^-/- mice showed an upregulation of the anti-oxidative stress response. β₇^-/- 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 β₇^-/- 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, β₇-Integrin unexpectedly exerts protective effects. β₇^-/- mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of β₇-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, β₇-Integrin-deficiency results in increased steatohepatitis.

Keywords: MAdCAM-1; Non-alcoholic steatohepatitis (NASH); β(7)-Integrin.