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      Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies

      1 , 2

      Cellular and Molecular Immunology

      Nature Publishing Group

      macrophage, chemokine, liver fibrosis, monocyte, microbiome

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          Macrophages represent a major cell type of innate immunity and have emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Hepatic macrophages consist of Kupffer cells, which are originated from the fetal yolk-sack, and infiltrated bone marrow-derived monocytes/macrophages. Hepatic macrophages play a central role in maintaining homeostasis of the liver and in the pathogenesis of liver injury, making them an attractive therapeutic target for liver diseases. However, the various populations of hepatic macrophages display different phenotypes and exert distinct functions. Thus, more research is required to better understand these cells to guide the development of macrophage-based therapeutic interventions. This review article will summarize the current knowledge on the origins and composition of hepatic macrophages, their functions in maintaining hepatic homeostasis, and their involvement in both promoting and resolving liver inflammation, injury, and fibrosis. Finally, the current strategies being developed to target hepatic macrophages for the treatment of liver diseases will be reviewed.

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          Most cited references 133

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          Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis.

          Mononuclear phagocytes, including monocytes, macrophages, and dendritic cells, contribute to tissue integrity as well as to innate and adaptive immune defense. Emerging evidence for labor division indicates that manipulation of these cells could bear therapeutic potential. However, specific ontogenies of individual populations and the overall functional organization of this cellular network are not well defined. Here we report a fate-mapping study of the murine monocyte and macrophage compartment taking advantage of constitutive and conditional CX(3)CR1 promoter-driven Cre recombinase expression. We have demonstrated that major tissue-resident macrophage populations, including liver Kupffer cells and lung alveolar, splenic, and peritoneal macrophages, are established prior to birth and maintain themselves subsequently during adulthood independent of replenishment by blood monocytes. Furthermore, we have established that short-lived Ly6C(+) monocytes constitute obligatory steady-state precursors of blood-resident Ly6C(-) cells and that the abundance of Ly6C(+) blood monocytes dynamically controls the circulation lifespan of their progeny. Copyright © 2013 Elsevier Inc. All rights reserved.
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            A lineage of myeloid cells independent of Myb and hematopoietic stem cells.

            Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11b(high) monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80(bright) macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia--cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.
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              Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment.

              Macrophages are critical for innate immune defense and also control organ homeostasis in a tissue-specific manner. They provide a fitting model to study the impact of ontogeny and microenvironment on chromatin state and whether chromatin modifications contribute to macrophage identity. Here, we profile the dynamics of four histone modifications across seven tissue-resident macrophage populations. We identify 12,743 macrophage-specific enhancers and establish that tissue-resident macrophages have distinct enhancer landscapes beyond what can be explained by developmental origin. Combining our enhancer catalog with gene expression profiles and open chromatin regions, we show that a combination of tissue- and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages. The environment is capable of shaping the chromatin landscape of transplanted bone marrow precursors, and even differentiated macrophages can be reprogrammed when transferred into a new microenvironment. These results provide a comprehensive view of macrophage regulatory landscape and highlight the importance of the microenvironment, along with pioneer factors in orchestrating identity and plasticity.

                Author and article information

                Cell Mol Immunol
                Cell. Mol. Immunol
                Cellular and Molecular Immunology
                Nature Publishing Group
                May 2016
                24 February 2016
                1 May 2016
                : 13
                : 3
                : 316-327
                [1 ]Skaggs School of Pharmacy and Pharmaceutical Sciences and Integrated Immunology, University of Colorado Anschutz Medical Campus , Aurora, USA
                [2 ]Department of Medicine III, University Hospital Aachen , Aachen, Germany
                Author notes
                [* ] University of Colorado Anschutz Medical Campus , 12850 East Montview Blvd, Aurora, Colorado, USA. Email: cynthia.ju@
                [* ] Department of Medicine III, University Hospital Aachen , Pauwelsstrasse 30, 52074 Aachen, Germany. Email: frank.tacke@
                Copyright © 2016 Chinese Society of Immunology and The University of Science and Technology

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                macrophage, microbiome, monocyte, liver fibrosis, chemokine


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