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Role of Macrophages in Experimental Liver Injury and Repair in Mice (Review)

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Role of Macrophages in Experimental Liver Injury and Repair in Mice (Review) EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 3835-3847, 2019 Role of macrophages in experimental liver injury and repair in mice (Review) XIAOTIAN DONG, JINGQI LIU, YANPING XU and HONGCUI CAO State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China Received July 9, 2018; Accepted December 6, 2018 DOI: 10.3892/etm.2019.7450 Abstract. Liver macrophages make up the largest proportion 1. Introduction of tissue macrophages in the host and consist of two dissimilar groups: Kupffer cells (KCs) and monocyte-derived macrophages Macrophages, originating from monocytic precursors, have (MoMø). As the liver is injured, KCs sense the injury and initiate multiple functions and are widely known for their phagocytic inflammatory cascades mediated by the release of inflamma- capacity, antigen-presenting function and active secretory tory cytokines and chemokines. Subsequently, inflammatory properties. Once localized in the liver, macrophages exhibit monocytes accumulate in the liver via chemokine-chemokine high phagocytic activity to remove endotoxins and pernicious receptor interactions, resulting in massive inflammatory MoMø substances from the portal vein. Resident tissue macrophages infiltration. When live r injury ceases, restorative macrophages, and inflammatory monocytes recruited from bone marrow derived from recruited inflammatory monocytes (lymphocyte have a dual role in organ damage induced by various factors, antigen 6 complex, locus Chi monocytes), promote the resolution including infection, auto-immune disorders and mechanical of hepatic damage and fibrosis. Consequently, a large number or toxic injuries (1). Following liver injury, the resident liver of studies have assessed the mechanisms by which liver macro- macrophages are activated and exert pro-inflammatory, phages exert their opposing functions at different time-points pro-wound healing and restorative effects at different stages during liver injury. The present review primarily focuses on the of hepatic injury and the repair response (2). Studies using diverse functions of macrophages in experimental liver injury, animal models of chemical‑induced liver injury have identified fibrosis and repair in mice and illustrates how macrophages may macrophages as the key regulators of liver repair and regenera- be targeted to treat liver disease. tion, or fibrosis. In the present review, the various functions of macrophages in hepatic toxicity are illustrated. Contents 2. Macrophages 1. Introduction Macrophages are widely distributed phagocytic innate 2. Macrophages immune cells that have essential roles in tissue homeostasis 3. Role of macrophages in carbon tetrachloride‑induced liver and the host defence. The diverse tissue macrophage popula- injury, fibrosis and repair tions resident in most tissues of the body mainly originate 4. Role of macrophages in other non-CCl4 induced liver from the yolk sac in the process of embryogenesis, and injury animal models certain tissue macrophages are developed from fetal liver and 5. Therapeutic potential of macrophages hematopoietic progenitors at later time-points (3). For closed 6. Conclusions tissues, resident macrophages [e.g., lung alveolar macrophages and liver Kupffer cells (KCs)] mostly originate from fetal liver monocytes (4). Liver macrophages, accounting for 20-35% of hepatic non-parenchymal cells, make up the largest proportion (80-90%) of tissue macrophages in the host and are an essential constituent of the mononuclear phagocytic system (5). They Correspondence to: Professor Hongcui Cao, State Key Laboratory consist of two distinct populations: ‘Sessile’ KCs and motile for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, liver macrophages, named as monocyte-derived macrophages 79 Qingchun Road, Hangzhou, Zhejiang 310003, P.R. China (MoMø). The former, ‘sessile’ KCs, function as a scavenger to E-mail: [email protected] remove microorganisms and cell debris from the blood and clear aged erythrocytes. Furthermore, in adult tissues, they Key words: liver injury, macrophage, inflammation, immune undergo self-maintenance independently of hematopoietic function, mouse stem cells. Phenotypes of ‘sessile’ KCs are characterized as F4/80hi, CD11blo, CD169+, CD68+, Mac-2+ and CD80lo/‑ (6-8). The latter, motile liver macrophages are distinct from ‘sessile’ 3836 DONG et al: IMMUNE FUNCTION OF MACROPHAGES KCs in terms of local migration to participate in inflammatory exert numerous functional roles (1). Carbon tetrachloride (CCl4) foci (9). The major function of motile liver macrophages is toxicity has various distinct ultimate outcomes, including hepa- immune surveillance. Furthermore, these cells directly origi- tocyte necrosis, liver fibrosis and cirrhosis, or even cancer (14). nate from circulating monocytes. Surface expression marker Tissue repair is a complex process influenced by intricate cellular profiles of motile liver macrophages include F4/80int, CD11bhi signaling pathways consisting of various cytokines, chemokines, and CD80hi (8). These characteristics suggest that liver macro- nuclear receptors and growth factors that may trigger the expres- phages have distinct liver‑specific gene expression patterns. sion of pro‑mitogenic genes and finally promote cell division (15). In spite of the widespread use of specific terms to define Hence, the mouse model of CCl4-induced hepatic injury or macrophage activation states [i.e., classically activated (M1) fibrosis is probably the best representative experimental model and alternatively activated (M2), no experimental standards for elucidating the various roles of liver macrophages in response are currently available for describing their activation (10). to liver injury or fibrosis (Fig. 1). The original terminology using M1 and M2 macrophage activation states is derived from different macrophage gene Monocyte recruitment. Blood monocytes represent circulating expression patterns stimulated with interferon (IFN)-γ/lipo- precursors of tissue dendritic cells and macrophages, and polysaccharide (LPS) or interleukin (IL)‑4/IL‑13 (11). Within may be divided into two major subsets in mice: Ly6C+/hi and this terminology, classically activated M1 macrophages (acti- Ly6C-/low monocytes. Ly6C+ mouse monocytes highly express vated by IFN‑γ, LPS or high‑mobility group protein 1) are the chemokine receptors C-C motif chemokine receptor 1 functionally pro‑inflammatory, microbicidal and tumoricidal. (CCR1) and CCR2, whereas murine Ly6C- monocytes mainly Furthermore, they exhibit anti‑proliferative and cytotoxic express CCR5 and C-X3-C motif chemokine receptor 1 activity. Virtually all of these features are produced by the (CX3CR1) (16). The early recruitment of Ly6C+ mono- release of numerous inflammatory cytokines, including cytes, but not of Ly6C- monocytes, to the liver upon toxic tumor necrosis factor (TNF)-α, IL-1, IL-6 and IL-12/23 injury is mediated by CCR2 [ligand: C‑C motif chemokine (p40). By contrast, alternatively activated M2 macrophages ligand 2 (CCL2)] and CCR8 (ligand: CCL1). Studies using downregulate the inflammatory response and facilitate tissue CCR2-deficient (CCR2-/-) and monocyte chemoattractant repair by increasing the expression of IL‑10, IL‑4/IL‑13 and protein (MCP)-1-/- mice or specific blockade suggested that transforming growth factor (TGF)-β, as well as vascular CCR2 mediates the early accumulation of inflammatory endothelial growth factor (VEGF)-α. Due to the complex Ly6C+ monocytes in the damaged murine liver (17). CCR8 is biological characteristics of macrophage subsets, M2 macro- also crucial for Ly6C+ monocyte infiltration into the injured phages are further subdivided to account for their differences: murine liver (18). Furthermore, Ly6C+ monocytes, migrating M2a, M2b and M2c activated by IL‑4/IL‑13, LPS/IL‑1β from the blood to tissues affected by infection, may differen- and IL-10/glucocorticoids, respectively (12). However, the tiate into inflammatory macrophages in inflamed tissues (19). concept of the M1 and M2 definitions requires to be revised; Of note, Ly6C- monocytes have a more patrolling role at the this should include a reproducible experimental standard, endothelium in a lymphocyte function-associated antigen-1- minimal reporting standards, a definition of the activators and CX3CR1-dependent fashion, acting as scavengers and and markers of activation (10,13). In fact, macrophages orchestrating tissue repair (20), without inflammatory stimuli. display variable functions (e.g., initiation and perpetuation It was recently noted that Ly6C- monocytes do not represent a of inflammation, promotion of liver fibrosis and resolution distinct lineage, but instead originate from Ly6C+ monocytes of inflammation and fibrosis) in diverse microenvironments. regulated by CCAAT/enhancer binding protein β in the bone The plasticity of macrophage activation may be elucidated marrow and blood, and that the lifespan of Ly6C- monocytes by analyzing macrophage expression profiles. Furthermore, may be negatively controlled by Ly6C+ peripheral blood mono- it is noteworthy that the ‘restorative macrophages’ in the liver cytes (21). A systematic assessment of the differential roles of fibrosis resolution phase derived from recruited lymphocyte these monocyte subsets and their recruitment dynamics in antigen 6 complex, locus C (Ly6C)+ monocytes have a liver injury is required prior
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