Scavenger Receptors: Novel Roles in the Pathogenesis of Liver Inflammation and Cancer

Abstract

The scavenger receptor superfamily represents a highly diverse collection of evolutionarily-conserved receptors which are known to play key roles in host homeostasis, the most prominent of which is the clearance of unwanted endogenous macromolecules, such as oxidized low-density lipoproteins, from the systemic circulation. Members of this family have also been well characterized in their binding and internalization of a vast range of exogenous antigens and, consequently, are generally considered to be pattern recognition receptors, thus contributing to innate immunity. Several studies have implicated scavenger receptors in the pathophysiology of several inflammatory diseases, such as Alzheimer's and atherosclerosis. Hepatic resident cellular populations express a diverse complement of scavenger receptors in keeping with the liver's homeostatic functions, but there is gathering interest in the contribution of these receptors to hepatic inflammation and its complications. Here, we review the expression of scavenger receptors in the liver, their functionality in liver homeostasis, and their role in inflammatory liver disease and cancer.

Fig. 1

Scavenger receptors implicated in liver homeostasis and pathogenesis, including receptor class, shared structural domains, liver cell expression, and functional role within the liver. Functions shown in green are considered protective and those shown in red are considered detrimental. Context-dependent functions are indicated in black . Figure created using biorender.com. ALF, acute liver failure; DC, dendritic cells; EC, endothelial cell; EGF, epidermal growth factor; HCC hepatocellular carcinoma; HCV, hepatitis C virus; HDL, high-density lipoprotein; HSC, hepatic stellate cell; LAMP, lysosome-associated membrane glycoprotein; LSEC, liver sinusoidal endothelial cell; Mϕ, macrophage; M _Ø , monocyte; NK, natural killer cell; NKT, natural killer T cell; oxLDL, oxidized low-density lipoprotein; PRR, pattern recognition receptor; SR, scavenger receptor; TAM, tumor-associated macrophage; TEM, transendothelial migration; T _eff , T effector cell; T _reg , regulatory T cell.

Fig. 2

Scavenger receptors represent valid therapeutic targets and are often valuable for use as biomarkers of liver disease, either in their soluble form in the serum or their cellular form within the tissues. This table summarizes the translational stage of each scavenger receptor, including in vitro and in vivo preclinical models and ongoing or completed clinical trials. Figure created using biorender.com. ALF, acute liver failure; ALI, acute liver injury; CEA, carcinoembryonic antigen; FA, fatty acid; Hb-Hp, hemoglobin–haptoglobin complex; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; hLSEC, human liver sinusoidal endothelial cells; hMDMs, human monocyte-derived macrophages; HSC, hepatic stellate cells; mBMDMs, murine bone marrow-derived macrophages; mLSEC, murine liver sinusoidal endothelial cells; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NS3, nonstructural 3 protein; oxLDL, oxidized low-density lipoprotein; TAM, tumor-associated macrophage; T _reg , regulatory T cells; TWEAK, tumor necrosis factor-like weak inducer of apoptosis.

Fig. 3

Scavenger receptors have widespread and pleiotropic roles in liver pathophysiology. Acute or chronic liver injury causes inflammation, which if unresolved, can progress to fibrosis or acute liver failure, respectively. Inflammation is underpinned by leukocyte recruitment across the sinusoidal endothelium, and several scavenger receptors have been implicated in adhesion or transmigration steps of the leukocyte adhesion cascade. Although early fibrosis can regress, if noxious stimulus is not removed and liver injury persists, fibrosis will progress to cirrhosis and/or hepatocellular carcinoma (HCC). Figure created using biorender.com.