title: β7-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis.
abstract: 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.
  
  
  
  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.
  
  
  
  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 (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 β7-/-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, 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.
  
  
  
  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.
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Drescher
authors.affiliation: Department of Pediatrics, University Hospital, RWTH Aachen, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schippers
authors.affiliation: Department of Pediatrics, University Hospital, RWTH Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clahsen
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.
authors.forename: Hacer
authors.initials: H
authors.lastname: Sahin
authors.affiliation: Institute of Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Noels
authors.affiliation: Institute of Medical Microbiology, University Hospital, RWTH Aachen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hornef
authors.affiliation: Department of Pediatrics, University Hospital, RWTH Aachen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.
authors.forename: Konrad L
authors.initials: KL
authors.lastname: Streetz
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany. Electronic address: dkroy@ukaachen.de.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Kroy
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002796:Choline Deficiency / Q000150:complications; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009088:Mucoproteins; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress
chemical_list: D015815:Cell Adhesion Molecules; D039641:Integrin beta Chains; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C091368:integrin beta7; D008715:Methionine
keywords: MAdCAM-1; Non-alcoholic steatohepatitis (NASH); β(7)-Integrin