Dataset Information

Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases.

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.

SUBMITTER: van der Heide D

PROVIDER: S-EPMC6901832 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases.

van der Heide Daphne D Weiskirchen Ralf R Bansal Ruchi R

Frontiers in immunology 20191203

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 ...[more]

PMID: 31849997

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Project description:Background & aims: The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model.MethodsAdipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by i.p. administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed.ResultsPatients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids.ConclusionsPro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD.Impact and implicationsWe report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.

Dataset Information

Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases.

Publications

Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases.

Similar Datasets

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