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Introduction Lymphocytes are recruited via the unique hepatic sinusoidal channels during chronic inflammatory liver diseases. This low shear vascular bed is lined by hepatic sinusoidal endothelium (HSEC) which lacks certain conventional adhesion molecules leading us to look for novel receptors involved in lymphocytes recruitment. HSEC express several receptors found on lymphatic endothelium including the scavenger receptor CLEVER-1 which has been implicated in lymphocyte migration to lymph nodes. Aim We now show that CLEVER-1 is upregulated on human hepatic sinusoidal endothelium where it is involved in lymphocyte transendothelial migration. Method We studied the expression of CLEVER-1 in normal and diseased human liver tissue and on isolated human sinusoidal endothelial cells. We used isolated HSEC in flow adhesion assays to study the functional role of CLEVER-1 in lymphocyte subset recruitment. Immunofluorescent staining and confocal microscopy were used to characterise the transmigration of lymphocytes across HSEC under conditions of flow. Results CLEVER-1 was expressed at high levels within the sinusoids of chronically inflamed livers and hepatocellular carcinomas as well as at other sites of lymphocyte recruitment including neo-vessels and portal associated lymphoid tissue. Flow-based adhesion assays using human HSEC demonstrated that CLEVER-1 mediates transmigration of CD4 but not CD8T cells with strong preferential activity for FoxP3+regulatory T cells. Confocal microscopy demonstrated that a large proportion of CD4 Treg transmigrated via the transcellular route through CLEVER-1 lined channels within the endothelial cell. Conclusion This is the first report to implicate a specific adhesion molecule in the recruitment of T regulatory cells to tissue. CLEVER-1 appears to mediate the transcellular migration of Tregs through hepatic sinsuoids and is an organ specific target for therapy aimed at modulating Treg recruitment to the liver. [ABSTRACT FROM PUBLISHER]

Objective: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expression, function and enzymatic activation of the ectoenzyme VAP-1 in patients with PSC., Design: We examined VAP-1 expression in patients with PSC, correlated levels with clinical characteristics and determined the functional consequences of enzyme activation by specific enzyme substrates on hepatic endothelium., Results: The intrahepatic enzyme activity of VAP-1 was elevated in PSC versus immune-mediated disease controls and non-diseased liver (p<0.001). The adhesion of gut-tropic α4β7 + lymphocytes to hepatic endothelial cells in vitro under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a number of natural VAP-1 substrates tested, cysteamine-which can be secreted by inflamed colonic epithelium and gut bacteria-was the most efficient (yielded the highest enzymatic rate) and efficacious in its ability to induce expression of functional mucosal addressin cell adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated patient cohort with PSC, elevated serum soluble (s)VAP-1 levels predicted poorer transplant-free survival for patients, independently (HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis., Conclusions: VAP-1 expression is increased in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and elevated levels of its circulating form predict clinical outcome in patients., Competing Interests: Competing interests: PJT is the recipient of a Wellcome Trust Clinical Research Fellowship (Grant ID: 099907/Z/12/Z). PJT, JT, PE, RP, EL, GMH, DHA and CJW received institutional salary support from the NIHR Birmingham Liver Biomedical Research Centre. This paper presents independent research supported by the Birmingham NIHR Liver Biomedical Research Centre based at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)