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Review
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The Role of Stabilin-1 in Lymphocyte Trafficking and Macrophage Scavenging in the Liver Microenvironment

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Review

The Role of Stabilin-1 in Lymphocyte Trafficking and Macrophage Scavenging in the Liver Microenvironment

Daniel A Patten et al. Biomolecules.

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.

Keywords: Fibrosis; Inflammation; Liver; Stabilin-1.

Conflict of interest statement

S.S. receives consultancy fees from Faron Pharmaceuticals.

Figures

Figure 1
Figure 1
Lymphocyte trafficking in chronic liver disease. Lymphocyte recruitment from the circulation into liver tissue occurs within the low shear specialized channels of the hepatic sinusoids that are lined by hepatic sinusoidal endothelial cells and the macrophage liver resident population, the Kupffer cells. During liver injury, the signals of damaged epithelial cells lead to activation of hepatic stellate cells in the Space of Disse underneath the sinusoidal endothelium. The sinusoidal endothelium itself is activated and upregulates the expression of adhesion molecules, which promote the recruitment of lymphocytes from circulation in an organ specific manner. This involves an adhesion cascade where lymphocytes in circulation undergo a tethering step leading to firm adhesion and activation on the endothelial surface, followed by their transendothelial migraton into liver tissue.
Figure 2
Figure 2
The molecular mechanisms of lymphocyte trafficking in liver disease. The recruitment of lymphocytes in the hepatic sinusoids is mediated by a combination of surface receptors and chemoattractant cytokines. In conventional recruitment, lymphocytes undergo a rolling step that is mediated by selectins. Selectins are absent in the sinusoidal channels, and after a brief tethering, lymphocytes undergo activation and firm adhesion mediated by a combination of chemokines presented on the endothelium and binding to chemokine receptors on the lymphocyte surface (for example, the inflammatory chemokines CXCL9, 10, and 11 binding to the chemokine receptor CXCR3, or the chemokine CXCL16 binding to CXCR6). Following activation, the lymphocytes bind via integrins to intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The final step is transendothelial migration, which has been shown to be mediated by ICAM-1, vascular adhesion protein-1 (VAP-1), and stabilin-1.
Figure 3
Figure 3
The routes taken by lymphocytes during transendothelial migration. Detailed analysis of the last step of the adhesion cascade where lymphocytes cross the endothelial barrier have demonstrated that several routes can be taken. The conventional route is the paracellular route, where lymphocytes migrate directly between endothelial cellular junctions. The second route, which appears to occur in the liver at a high frequency, is the migration of lymphocytes directly through the body of the cell, termed the transcellular migration. This route of migration has been described in other microvascular beds including the lymphatics and bone marrow. An additional novel route has also been described where lymphocytes invade into the body of the endothelial cell and then migrate directly into the adjacent endothelial cell termed ‘intracellular crawling’. Stabilin-1 has been shown to contribute to both transcellular migration and intracellular crawling.
Figure 4
Figure 4
The scavenging role of stabilin maintains homeostasis in the liver by the uptake of products of oxidative stress. Stabilin-1 contributes to the hepatic uptake of circulating oxidized low-density lipoproteins (oxLDLs). In the setting of stabilin-1 deficiency, these oxLDLs lead to a proinflammatory response specifically, leading to increased levels of the chemokine CCL3, which drives the proliferation of liver-resident fibroblasts and causes an increase in collagen fibres in the livers of stabilin-1 knockout mice.
Figure 5
Figure 5
Stabilin-1 expression on hepatic macrophages protects against excessive tissue damage from chronic oxidative stress. (A) In models of chronic liver injury, the repetitive damage to hepatocytes leads to oxidative stress and lipid peroxidation, which leads to the formation of malondialdheyde-lipoproteins (MDA-LDL), which accumulate in the liver. Stabilin-1 expression on hepatic macrophages leads to the uptake of MDA-LDL, which leads to the formation of ceroid-laden macrophages that are found at sites of scarring. The active uptake of MDA-LDL by stabilin-1 positive macrophages suppresses the release of pro inflammatory mediators such as CCL3. (B) In the setting of stabilin-1 deficiency, there is a loss of these ceroid-laden macrophages and a lack of accumulation of MDA-LDL within hepatic macrophages. 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.

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