β7-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis
β7-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis
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DOI：
10.1016/j.jhep.2017.02.001
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发表时间：
2017-06-01
影响因子：
25.7
通讯作者：
Kroy, Daniela C.
中科院分区：
文献类型：
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作者：
Drescher, Hannah K.;Schippers, Angela;Kroy, Daniela C.
背景与目的：非酒精性脂肪性肝炎（NASH）是西方国家慢性肝病的主要原因。目前尚不清楚浸润性白细胞如何影响NASH的发展。我们的研究旨在探讨归巢/受体，对粘膜地址素细胞粘附分子-1的作用，（MAdCAM-1）/β（7）-整合素对脂肪性肝炎模型中免疫细胞募集和疾病进展的影响。组成型β（7）-整联蛋白缺乏（β（-/-）（7））和MAdCAM-1缺陷（MAdCAM-1（-/-））小鼠喂食高脂饮食（HFD）26周或蛋氨酸胆碱缺乏饮食（MCD）4周。β（-/-）（7）小鼠在HFD和MCD治疗期间显示出更早和更渐进的脂肪性肝炎，而MAdCAM-1（-/-）小鼠显示出较少的组织形态学变化。β（-/-）（7）小鼠的抗氧化应激反应明显较弱，这反映在转录因子核因子（红细胞衍生2）样2（Nrf 2）和血红素氧合酶-1（HO-1）的显著下调。此外，更强的二氢乙锭染色显示β（-/-）（7）动物的氧化应激反应增加。相比之下，MAdCAM-1（-/-）小鼠表现出抗氧化应激反应的上调。β（-/-）（7）动物表现出较强的炎性细胞肝浸润，尤其是中性粒细胞，反映了较早的脂肪性肝炎开始。在MAdCAM-1（-/-）小鼠中，调节性T细胞（T-Reg）标志物的表达以及抗炎巨噬细胞的数量显著增强。这些变化最终导致β（-/-）（7）小鼠中更早和更强的胶原积累，而MAdCAM-1（-/-）小鼠受到保护免于纤维化的启动。结论：粘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果。虽然MAdCAM-1促进脂肪性肝炎，β（7）-整合素出乎意料地发挥保护作用。β（-/-）（7）小鼠显示较早的脂肪性肝炎开始和显著更强的纤维化进展。因此，β（7）-整合素和它们的受体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。MAdCAM-1的缺失对NASH的发展具有有益作用-表现为肝脏氧化应激减少和炎症减少。相反，β（7）-整合素缺乏导致脂肪性肝炎增加。(C)2017年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
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)/beta(7)-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model.Methods: Constitutive beta(7)-Integrin deficient (beta(-/-)(7)) and MAdCAM-1 deficient (MAdCAM-1(-/-)) mice were fed a high fat diet (HFD) for 26 weeks or methionine-choline-deficient-diet (MCD) for 4 weeks.Results: beta(-/-)(7) 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 beta(-/-)(7) 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 beta(-/-)(7) animals. In contrast, MAdCAM-1(-/-) mice showed an upregulation of the anti-oxidative stress response. beta(-/-)(7) 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 beta(-/-)(7) 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, beta(7)-Integrin unexpectedly exerts protective effects. beta(-/-)(7) mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of beta(7)-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 nonalcoholic 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, beta(7)-Integrin-deficiency results in increased steatohepatitis. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.