Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.
Department of Pediatrics, University Hospital, RWTH Aachen, Germany.
J Hepatol. 2017 Jun;66(6):1251-1264. doi: 10.1016/j.jhep.2017.02.001. Epub 2017 Feb 10.
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)/β-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model.
Constitutive β-Integrin deficient (β) and MAdCAM-1 deficient (MAdCAM-1) mice were fed a high fat diet (HFD) for 26weeks or methionine-choline-deficient-diet (MCD) for 4weeks.
β 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 β 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 β animals. In contrast, MAdCAM-1 mice showed an upregulation of the anti-oxidative stress response. β animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (T) 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 β 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, β-Integrin unexpectedly exerts protective effects. β mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of β-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, β-Integrin-deficiency results in increased steatohepatitis.
非酒精性脂肪性肝炎（NASH）是西方国家慢性肝病的主要原因。浸润的白细胞如何影响 NASH 的发展尚不清楚。我们的研究旨在调查归巢/受体对黏膜地址素细胞黏附分子-1（MAdCAM-1）/β-整合素在脂肪性肝炎模型中免疫细胞募集和疾病进展中的作用。
固有β-整合素缺陷（β）和 MAdCAM-1 缺陷（MAdCAM-1）小鼠分别用高脂肪饮食（HFD）喂养 26 周或蛋氨酸-胆碱缺乏饮食（MCD）喂养 4 周。
β 小鼠在 HFD 和 MCD 治疗期间表现出更早和更进展性的脂肪性肝炎，而 MAdCAM-1 小鼠的组织形态学变化较小。抗氧化应激反应在β 小鼠中明显较弱，表现为核因子（红系衍生 2）样 2（Nrf2）和血红素加氧酶-1（HO-1）转录因子的显著下调。此外，β 动物中二氢乙啶染色更强，表明氧化应激反应增强。相反，MAdCAM-1 小鼠表现出抗氧化应激反应的上调。β 动物肝内炎症细胞浸润更强，特别是中性粒细胞，反映出更早的脂肪性肝炎起始。调节性 T 细胞（T）标志物的表达以及抗炎巨噬细胞的数量在 MAdCAM-1 小鼠中显著增加。这些变化最终导致β 小鼠胶原积累更早且更强，而 MAdCAM-1 小鼠则免受纤维化起始的影响。
黏附分子介导的效应细胞迁移有助于 HFD 和 MCD 模型中脂肪性肝炎的结局。虽然 MAdCAM-1 促进脂肪性肝炎，但β-整合素出人意料地发挥保护作用。β 小鼠表现出更早的脂肪性肝炎起始和更强的纤维化进展。因此，β-整合素及其受体 MAdCAM-1 的相互作用为脂肪性肝炎的治疗干预提供了新的靶点。
黏膜地址素细胞黏附分子 1（MAdCAM-1）在饮食诱导的非酒精性脂肪性肝炎（NASH）时在肝脏中表达。MAdCAM-1 的缺失对 NASH 的发展有有益的影响，表现为肝氧化应激和炎症减少。相比之下，β-整合素缺陷导致脂肪性肝炎增加。
