Hannah K Drescher1, Angela Schippers2, Thomas Clahsen2, Hacer Sahin1, Heidi Noels3, Mathias Hornef4, Norbert Wagner2, Christian Trautwein1, Konrad L Streetz1, Daniela C Kroy5. 1. Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany. 2. Department of Pediatrics, University Hospital, RWTH Aachen, Germany. 3. Institute of Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany. 4. Institute of Medical Microbiology, University Hospital, RWTH Aachen, Germany. 5. Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany. Electronic address: dkroy@ukaachen.de.
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 (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. 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.
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 (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. 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.
Authors: Mohsen Malehmir; Dominik Pfister; Suchira Gallage; Marta Szydlowska; Donato Inverso; Elena Kotsiliti; Valentina Leone; Moritz Peiseler; Bas G J Surewaard; Dominik Rath; Adnan Ali; Monika Julia Wolf; Hannah Drescher; Marc E Healy; Daniel Dauch; Daniela Kroy; Oliver Krenkel; Marlene Kohlhepp; Thomas Engleitner; Alexander Olkus; Tjeerd Sijmonsma; Julia Volz; Carsten Deppermann; David Stegner; Patrick Helbling; César Nombela-Arrieta; Anahita Rafiei; Martina Hinterleitner; Marcel Rall; Florian Baku; Oliver Borst; Caroline L Wilson; Jack Leslie; Tracy O'Connor; Christopher J Weston; Abhishek Chauhan; David H Adams; Lozan Sheriff; Ana Teijeiro; Marco Prinz; Ruzhica Bogeska; Natasha Anstee; Malte N Bongers; Mike Notohamiprodjo; Tobias Geisler; Dominic J Withers; Jerry Ware; Derek A Mann; Hellmut G Augustin; Alexandros Vegiopoulos; Michael D Milsom; Adam J Rose; Patricia F Lalor; Josep M Llovet; Roser Pinyol; Frank Tacke; Roland Rad; Matthias Matter; Nabil Djouder; Paul Kubes; Percy A Knolle; Kristian Unger; Lars Zender; Bernhard Nieswandt; Meinrad Gawaz; Achim Weber; Mathias Heikenwalder Journal: Nat Med Date: 2019-04-01 Impact factor: 53.440
Authors: Angela Schippers; Jessica Hübel; Felix Heymann; Thomas Clahsen; Sreepradha Eswaran; Sarah Schlepütz; Robin Püllen; Nikolaus Gaßler; Klaus Tenbrock; Frank Tacke; Norbert Wagner Journal: Cell Mol Gastroenterol Hepatol Date: 2020-12-13
Authors: Ravi P Rai; Yunshan Liu; Smita S Iyer; Silvia Liu; Biki Gupta; Chirayu Desai; Pradeep Kumar; Tekla Smith; Aatur D Singhi; Asma Nusrat; Charles A Parkos; Satdarshan P Monga; Mark J Czaja; Frank A Anania; Reben Raeman Journal: J Hepatol Date: 2020-06-12 Impact factor: 25.083
Authors: Sreepradha Eswaran; Anshu Babbar; Hannah K Drescher; Thomas C A Hitch; Thomas Clavel; Moritz Muschaweck; Thomas Ritz; Daniela C Kroy; Christian Trautwein; Norbert Wagner; Angela Schippers Journal: Int J Mol Sci Date: 2021-07-07 Impact factor: 5.923
Authors: Jae Yeon Kim; Ji Hye Jun; Soo Young Park; Seong Wook Yang; Si Hyun Bae; Gi Jin Kim Journal: Int J Mol Sci Date: 2019-10-24 Impact factor: 5.923