Abstract
Hepatic macrophages play a central role in maintaining homeostasis in the liver, as well as in the initiation and progression of liver diseases. Hepatic macrophages are mainly derived from resident hepatic macrophages called Kupffer cells or circulating bone marrow-derived monocytes. Kupffer cells are self-renewing and typically non-migrating macrophages in the liver and are stationed in the liver sinusoids in contrast to macrophages originating from circulating monocytes. Kupffer cells regulate liver homeostasis by mediating immunity against non-pathogenic blood-borne molecules, while participating in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes present in the vasculature. Monocyte-derived macrophages infiltrate into the liver tissue when metabolic or toxic damage instigates and are likely dispensable for replenishing the macrophage population in homeostasis. In recent years, different populations of hepatic macrophages have been identified with distinct phenotypes with discrete functions, far beyond the central dogma of M1 and M2 macrophages. Hepatic macrophages play a central role in the pathogenesis of acute and chronic liver failure, liver fibrosis, non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and hepatocellular carcinoma, as well as in disease resolution. The understanding of the role of hepatic macrophages in liver diseases provides opportunities for the development of targeted therapeutics for respective malignancies. This review will summarize the current knowledge of the hepatic macrophages, their origin, functions, their critical role in maintaining homeostasis and in the progression or resolution of liver diseases. Furthermore, we will provide a comprehensive overview of the therapeutic targeting strategies against hepatic macrophages developed for the treatment of liver diseases.
Highlights
The liver is the largest gland in the human body, weighing about 1.5 kg in an adult
We present the insights on hepatic macrophages [collectively referred to as resident Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs)], a heterogeneous population of immune cells that originate from different sources [3]
This study suggests that myeloid cells, especially macrophages, adapt their phenotype in response to metabolic microenvironment, indicating the metabolic reprogramming of macrophages in non-alcoholic steatohepatitis (NASH)
Summary
The liver is the largest gland in the human body, weighing about 1.5 kg in an adult. It plays an important role in metabolism and mediate several functions including glycogen storage, plasma protein synthesis, and drug detoxification. Hepatic immune tolerance is mostly dependent on the interaction between KCs and Tregs to create a local suppressive microenvironment, while the recruitment of MoMFs and crosstalk between hepatic stellate cells and macrophages are important determinant for the disease progression/pathogenesis, and tissue regeneration following liver injury. Bartneck and colleagues showed that dexamethasone-loaded liposomes were efficient in vivo by ameliorating inflammatory liver diseases in a model of acute hepatitis and in chronic carbon tetrachloride (CCl4)-based chronic toxic liver injury This approach resulted in a M2 activation profile of macrophages and with a significant reduction in the number of T cells in the liver van der Heide et al. CCR2 antagonists Cenicriviroc, propagermanium CCL2 antagonist mNOX-E36 CCR5 antagonist Miraviroc. Anti-inflammatory, anti-fibrotic Defected TLR9 signaling, decreased tumor cell proliferation Inhibits acute liver injury and bacterial translocation Attenuates DAMPs/PAMPs mediated liver injury Immuno-modulatory
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