肝巨噬细胞在肝纤维化中的发病机制和潜在的治疗靶点

StephenW

BMJ Open Gastro 2016; 3:e000079 doi:10.1136/bmjgast-2016-000079
Hepatic macrophages in liver fibrosis: pathogenesis and potential therapeutic targets
Hai Li1, Hong You2, Xu Fan3, Jidong Jia2,
Author Affiliations
1Department of Hepatopancreatobiliary and Splenic Medicine, Affiliated Hospital, Logistics University of People's Armed Police Force, Tianjin, People's Republic of China
2Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, People's Republic of China
3State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
Received:
10 January 2016
Accepted:
18 April 2016
Published Online:
25 May 2016
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/


Abstract

Hepatic macrophages account for the largest non-parenchymal cell population in the liver. Recent studies have found that hepatic macrophages have different functions in different stages of experimental liver fibrosis. Some studies found that there are different types of hepatic macrophages in the liver, although others have suggested that hepatic macrophages could switch to different phenotypes in different environments. Many studies demonstrated that while hepatic macrophages promoted fibrosis through the recruitment of proinflammatory immune cells, and the secretion of proinflammatory cytokines and chemokines in the early stages, these also promoted the resolution of hepatic fibrosis through the secretion of matrix metalloproteinases in the late stages. This article will review the current role played by hepatic macrophages in liver fibrosis and the potential therapeutic targets that modulate hepatic macrophages.
Keywords: HEPATIC FIBROSIS, MACROPHAGES, IMMUNOLOGY IN HEPATOLOGY
Introduction
Section:
Previous sectionNext section

Hepatic fibrosis is a dynamic process of repairing chronic liver injuries that may lead to cirrhosis and significant morbidity and mortality.1 Chronic necroinflammation activates hepatic stellate cells (HSCs) into myofibroblast-like cells, and the latter cells produce excessive extracellular matrix (ECM). Hepatic macrophages are a heterogeneous population of immune cells that perform diverse functions in homeostasis, and the progression and regression of chronic liver diseases. Recent studies with animal models of toxic or cholestatic liver fibrosis showed that hepatic macrophages can promote fibrogenesis via the initiation of fibrosis and sustain the phases of liver fibrosis,2 and can also promote fibrinolysis in the resolution phase.3

In this review, we will summarise the current understanding of the ambivalent roles played by macrophages in liver fibrosis, and will explore the potential targets of hepatic macrophages for treating liver fibrosis.4
The roles of hepatic macrophages in the pathogenesis of liver fibrosis

Hepatic macrophages play a central role in the pathogenesis of chronic liver injury, including inflammation and fibrosis.5 The phagocytic receptors in hepatic macrophages can be divided into membrane surface receptors and intracellular receptors.6 All of these receptors recognise and activate downstream molecules through different signalling pathways, thereby becoming involved in the processes of inflammation and fibrosis.7 8

Macrophages have different effects if their target cells are different. For example, phagocytosis of red blood cells causes iron deposition and induces oxidative stress reactions, which in turn promote inflammation and fibrosis; phagocytosis of collagen-producing cells and cell debris reduces inflammation and liver fibrosis. Furthermore, phagocytosis of apoptotic liver cells does not change the secretion of proinflammatory factors, although phagocytosis of necrotic liver cells causes the secretion of proinflammatory cytokines.9 This phenomenon may explain why macrophages do not promote fibrotic responses in normal conditions despite the fact that apoptosis of liver cells happens every day,10 11 whereas hepatic macrophages produce inflammatory responses and liver fibrosis when hepatocyte necrosis occurs.12–17

A recent study showed that macrophage migration inhibitory factor (MIF) plays an important role in the early stages of liver fibrosis.6 18 CCL4-induced liver fibrosis was more severe in MIF gene knockout mice than in wild-type mice. Some studies also found that sustained activation of hepatic nuclear factor κB (NFκB) in macrophages led to liver inflammation and fibrosis,8 19 whereas killing hepatic macrophages significantly reduced NFκB activity and inflammation and fibrosis in the liver.7

Under the effects of tumour necrosis factor (TNF) and transforming growth factor β1 (TGF-β1), and C-C motif chemokine receptor 9 (CCR9) and C-C motif chemokine ligand 25 (CCL25), blood mononuclear cells accumulate in the liver and turn into classical macrophages (M1).20 21 Some other molecules, such as CCL215 22 and monocyte chemotactic protein 1 (MCP-1) are also involved in the chemotaxis of M1 proinflammatory macrophages, and thereby play an important role in the recruitment of Ly-6C+ monocytes in liver fibrosis induced by CCL4.22 23 Other studies also suggest that hepatic macrophage promoted liver fibrosis is mediated by CCL2, CCR8 and CCR9, and maintains NFκB activation in the early stage.24 25

Many studies have suggested that hepatic macrophages have a two-way regulatory function2 in liver fibrosis; hepatic macrophages promote fibrosis through the recruitment of proinflammatory immune cells and the secretion of proinflammatory cytokines and chemokines in the early stages, whereas in the late stages, they promote the resolution of hepatic fibrosis through the secretion of matrix metalloproteinases (MMPs).
The classification of hepatic macrophages in liver fibrosis

StephenW

BMJ Open Gastro 2016; 3：e000079 doi：10.1136 / bmjgast-2016-000079
肝巨噬细胞在肝纤维化中的发病机制和潜在的治疗靶点
海丽1，洪友2，徐凡3，吉东佳2，
作者联盟
中华人民共和国天津市人民武装力量物流大学附属医院肝胆胰外科，
2中国北京市资本大学北京友谊医院肝脏研究中心
北京市辐射医学研究所北京蛋白质组学研究中心蛋白质组学国家重点实验室，北京，中华人民共和国
收稿日期：
2016年1月10日
公认：
2016年4月18日
在线发布：
2016年5月25日
这是根据知识共享署名非商业性（CC BY-NC 4.0）许可发布的开放获取文章，允许其他人分发，混搭，适应，非商业性的工作，并对其衍生作品进行不同的许可条款，原始作品被正确引用，使用非商业性。见：http://creativecommons.org/licenses/by-nc/4.0/


抽象

肝巨噬细胞占肝脏中最大的非实质细胞群体。最近的研究发现肝巨噬细胞在实验性肝纤维化的不同阶段具有不同的功能。一些研究发现，肝脏中存在不同类型的肝巨噬细胞，尽管其他研究人员认为肝巨噬细胞可以在不同环境中转变为不同的表型。许多研究表明，虽然肝巨噬细胞通过募集促炎免疫细胞促进纤维化，并且在早期阶段分泌促炎细胞因子和趋化因子，但这些也通过晚期基质金属蛋白酶的分泌促进了肝纤维化的分解。本文将回顾肝巨噬细胞在肝纤维化中的作用及调控肝巨噬细胞的潜在治疗靶点。
关键词：HEPATIC FIBROSIS，MACROPHAGES，IMMUNOLOGY IN HEPATOLOGY
介绍
部分：
上一节下一节

肝纤维化是修复慢性肝损伤的动态过程，可能导致肝硬化和显着的发病率和死亡率1慢性坏死因子将肝星状细胞（HSC）激活成肌成纤维细胞样细胞，后者细胞产生过量的细胞外基质（ECM）。肝巨噬细胞是免疫细胞的异质群体，其在体内平衡中起着不同的功能，以及慢性肝脏疾病的进展和消退。近期有毒或胆汁淤积性肝纤维化动物模型的研究表明，肝巨噬细胞可以通过纤维化的发生促进纤维发生，维持肝纤维化的阶段，2并且还可以在分辨率阶段3促进纤维蛋白溶解。

在本次综述中，我们将总结目前对巨噬细胞在肝纤维化中发挥的矛盾作用的理解，并探讨肝巨噬细胞治疗肝纤维化的潜在靶点。
肝巨噬细胞在肝纤维化发病机制中的作用

肝巨噬细胞在慢性肝损伤的发病机制中发挥重要作用，包括炎症和纤维化。肝巨噬细胞中的吞噬受体可以分为膜表面受体和细胞内受体.6所有这些受体通过不同信号识别和激活下游分子途径，从而参与炎症和纤维化过程

如果巨噬细胞的靶细胞不同，则具有不同的作用。例如，红细胞吞噬会导致铁沉积并诱导氧化应激反应，从而促进炎症和纤维化;胶原蛋白产生细胞和细胞碎片的吞噬作用减少炎症和肝纤维化。此外，凋亡性肝细胞的吞噬不会改变促炎因子的分泌，尽管坏死性肝细胞的吞噬作用导致促炎细胞因子的分泌.9这种现象可能解释了为什么巨噬细胞在正常条件下不促进纤维化反应，尽管事实上细胞凋亡肝细胞每天发生10 11，而肝细胞坏死发生时肝巨噬细胞产生炎症反应和肝纤维化12-17

最近的一项研究表明，巨噬细胞迁移抑制因子（MIF）在肝纤维化的早期阶段起着重要的作用[6]。在MIF基因敲除小鼠中CCL4诱导的肝纤维化比野生型小鼠更严重。一些研究还发现，巨噬细胞中肝核因子κB（NFκB）的持续激活导致肝脏炎症和纤维化，而肝脏巨噬细胞的杀伤显着降低肝脏NFκB活性和炎症和纤维化。

在肿瘤坏死因子（TNF）和转化生长因子β1（TGF-β1）和CC基序趋化因子受体9（CCR9）和CC基序趋化因子配体25（CCL25）的作用下，血液单核细胞积聚在肝脏中，经典巨噬细胞（M1）.20 21其他分子，如CCL215 22和单核细胞趋化蛋白1（MCP-1）也参与M1促炎巨噬细胞的趋化性，从而在募集Ly-6C + CCL4.22诱导的肝纤维化中的单核细胞23其他研究还表明肝巨噬细胞促进肝纤维化是由CCL2，CCR8和CCR9介导的，并在早期维持NFκB活化.24 25

许多研究表明肝巨噬细胞在肝纤维化中具有双向调节功能2;肝巨噬细胞通过募集促炎免疫细胞和促炎细胞因子和趋化因子在早期阶段的分泌来促进纤维化，而在晚期阶段，它们通过基质金属蛋白酶（MMPs）的分泌来促进肝纤维化的分解。
肝纤维化肝巨噬细胞分类

StephenW

http://bmjopengastro.bmj.com/doi/full/10.1136/bmjgast-2016-000079