SCARF-1 promotes adhesion of CD4+ T cells to human hepatic sinusoidal endothelium under conditions of shear stress

Daniel A. Patten,Joanne M. Rose,Shishir Shetty,David H. Adams,Chris J. Weston,Sivesh K. Kamarajah,Emma L. Shepherd,Joseph Tickle

doi:10.1038/s41598-017-17928-4

Abstract

Liver-resident cells are constantly exposed to gut-derived antigens via portal blood and, as a consequence, they express a unique repertoire of scavenger receptors. Whilst there is increasing evidence that the gut contributes to chronic inflammatory liver disease, the role of scavenger receptors in regulating liver inflammation remains limited. Here, we describe for the first time the expression of scavenger receptor class F, member 1 (SCARF-1) on hepatic sinusoidal endothelial cells (HSEC). We report that SCARF-1 shows a highly localised expression pattern and co-localised with endothelial markers on sinusoidal endothelium. Analysis of chronically inflamed liver tissue demonstrated accumulation of SCARF-1 at sites of CD4+ T cell aggregation. We then studied the regulation and functional role of SCARF-1 in HSEC and showed that SCARF-1 expression by HSEC is regulated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS). Furthermore, SCARF-1 expression by HSEC, induced by proinflammatory and gut-derived factors acts as a novel adhesion molecule, present in adhesive cup structures, that specifically supports CD4+ T cells under conditions of physiological shear stress. In conclusion, we show that SCARF-1 contributes to lymphocyte subset adhesion to primary human HSEC and could play an important role in regulating the inflammatory response during chronic liver disease.

Highlights

The liver receives 75–80% of its blood supply from the gut and the cells of the liver are exposed to a vast array of microbial antigens
We demonstrate that immobilised recombinant humanSCARF-1 can directly interact with CD4+ T lymphocytes in the presence of vascular cell adhesion molecule (VCAM)-1 in vitro, and can support CD4+ T cell adhesion to Hepatic sinusoidal endothelial cells (HSEC) stimulated with TNFα and LPS, under conditions of physiological flow through a SCARF-1 rich adhesive cup-like structure containing adherent CD4+ T cells
Given the high sinusoidal expression of SCARF-1 in hepatocellular carcinoma (HCC) tumour, we investigated the effects of the tumourigenic growth factors, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) and found that they increased the cellular expression of SCARF-1 in HSEC, as determined by cell-based ELISA (Supplementary Figure 4a), without increasing transcription (Supplementary Figure 4b)

Summary

Introduction

The liver receives 75–80% of its blood supply from the gut and the cells of the liver are exposed to a vast array of microbial antigens. Scavenger receptors are a large superfamily of proteins first identified by their ability to bind and subsequently internalise oxidised low density lipoproteins (oxLDLs)[4] They are known to bind multiple endogenous and exogenous products[5], including a wide array of microbial antigens[6]. Hepatic sinusoidal endothelial cells (HSEC), which represent the second most abundant cell type in the human liver, express an array of scavenger receptors at high density consistent with their role in removing microbial antigens from the portal blood. SCARF-1 has been shown to bind modified low density lipoproteins (LDLs), acetylated-LDLs (acLDLs)[23], and acts as an endocytic receptor for a wide range of damage-associated products including heat-shock proteins (Hsps)[24,25,26] and apoptotic host cells via the C1q protein[27]. We demonstrate that immobilised recombinant human (rh)SCARF-1 can directly interact with CD4+ T lymphocytes in the presence of vascular cell adhesion molecule (VCAM)-1 in vitro, and can support CD4+ T cell adhesion to HSEC stimulated with TNFα and LPS, under conditions of physiological flow through a SCARF-1 rich adhesive cup-like structure containing adherent CD4+ T cells

Methods

Results

Conclusion