Abstract
Chronic liver diseases are a major global health burden, and cases of these conditions continue to rise in many countries. A diverse range of insults can lead to chronic liver disease, but they are all characterised by the infiltration and accumulation of immune cells within liver tissue and, if progressive, can lead to tissue fibrosis and cirrhosis. In this review, we focus on the role of stabilin-1 in two key processes that contribute to liver disease, namely, the recruitment of lymphocytes into liver tissue and the response of macrophages to tissue injury. Stabilin-1 is constitutively expressed on the sinusoidal endothelium of the liver and contributes to the homeostatic scavenging function of these cells. Epithelial damage in the context of chronic liver disease leads to the upregulation of stabilin-1 at sites of tissue injury, specifically at sites of immune cell recruitment and on subpopulations of hepatic macrophages. Functionally, stabilin-1 has been shown to mediate transendothelial migration of lymphocyte subsets in the setting of pro-inflammatory-activated human liver endothelium. In experimental models of liver fibrosis, stabilin-1 promotes the uptake of products of chronic oxidative stress by a subset of hepatic macrophages and suppresses their release of pro-inflammatory mediators that regulate tissue remodelling. These studies highlight the active contribution that scavenger receptors such as stabilin-1 can make in regulating chronic inflammation and tissue fibrosis, and their potential as novel therapeutic targets for these conditions.
Highlights
Concurrent with the widespread obesity epidemic and increasing alcohol consumption worldwide, chronic inflammatory liver diseases in adults are significantly contributing towards a global burden on human health; the incidence of liver disease in the UK alone has risen over 400 % since the 1970s to become the third most common cause of premature death [1]
Each disease aetiology elicits a specific pattern of injury, which is largely dependent on the site of initial damage; for example, non-alcoholic steatohepatitis (NASH) is triggered by lipotoxicity in hepatocytes, resulting in parenchymal inflammation [5], whereas autoimmune disease, primary sclerosing cholangitis (PSC), is driven by bile duct injury and characterised by portal inflammation, ductular proliferation and loss of bile duct function [6]
The stabilin-1-deficient hepatic macrophages are shifted to a pro-inflammatory phenotype including excessive release of CCL3, and this is associated with excessive scarring from activated liver fibroblasts and delayed healing after liver injury
Summary
Concurrent with the widespread obesity epidemic and increasing alcohol consumption worldwide, chronic inflammatory liver diseases in adults are significantly contributing towards a global burden on human health; the incidence of liver disease in the UK alone has risen over 400 % since the 1970s to become the third most common cause of premature death [1]. In addition to the increasing incidence of non-alcoholic steatohepatitis (NASH; fatty liver disease) and alcohol-related liver disease (ARLD) [2], other aetiologies, such as viral hepatitis and autoimmune liver diseases, are contributing to the rising occurrence of chronic liver disease [3,4]. Scarring, results from the activation of hepatic stellate cells, a population of liver-resident pericytes, which differentiate under inflammatory conditions to a myofibroblast phenotype, resulting in the production of extracellular matrix proteins [7]. In chronic liver diseases, sustained activation of hepatic stellate cells, perpetuated by the chronicity of the inflammatory insult, leads to the excessive accumulation of scar tissue within the liver, which culminates in loss of liver function, cirrhosis and, eventually, end-stage liver failure or hepatocellular cancer (HCC)
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