Return to sender: Lymphocyte trafficking mechanisms as contributors to primary sclerosing cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tree, characterised by stricturing bile duct disease and progression to liver fibrosis. The pathophysiology of PSC is still unknown. The concurrence with inflammatory bowel disease (IBD) in about 70% of cases has led to the hypothesis that gut-homing lymphocytes aberrantly traffic to the liver, contributing to disease pathogenesis in patients with both PSC and IBD (PSC-IBD). The discovery of mutual trafficking pathways of lymphocytes to target tissues, and expression of gut-specific adhesion molecules and chemokines in the liver has pointed in this direction. There is now increasing interest in using drugs that intervene with these trafficking pathways (e.g. vedolizumab, etrolizumab) for the treatment of PSC-IBD. In this review we discuss what is currently known about the immunological interactions between the gut and the liver in concomitant PSC and IBD, as well as potential therapeutic options for intervening in these mechanisms.

The Many Roles of Cell Adhesion Molecules in Hepatic Fibrosis

“…In these animal models, the effect of VAP-1 on hepatic immigration of leukocytes was also dependent on amine oxidase activity [171]. Amine oxidase generates chemical compounds like aldehyde, ammonia or H 2 O 2 , which can trigger NF-қB-dependent expression of CAMs in the liver, like ICAM-1, VCAM-1 or MAdCAM-1, further increasing leukocyte adhesion [124]. These results further point out that sinusoidal ECs capture leukocytes with the help of IgCAMs and VAP-1, rather than selectins.…”

“…These findings point out that an intact intrahepatic biliary network with normal bile secretion depends on functional E-cadherin and p120-catenin. Another interesting observation is that E-cadherin can bind to αEβ7-integrin [124]. This interaction could by mistake mediate the positioning of αEβ7-positive mucosal T cells near cholangiocytes and hepatocytes inducing a proinflammatory environment similar to MAdCAM-1 (see section on non-classical CAMs).…”

“…This interaction could by mistake mediate the positioning of αEβ7-positive mucosal T cells near cholangiocytes and hepatocytes inducing a proinflammatory environment similar to MAdCAM-1 (see section on non-classical CAMs). This effect might be further boosted by TGFβ as it upregulates mRNA levels of αE and β7 [124]. E-cadherin is also expressed in quiescent HSCs but gets lost when HSCs differentiate into myofibroblasts, which then instead express N-cadherin (Table 2) [125,126].…”

“…Vascular adhesion protein 1 (VAP-1) is a homodimeric transmembrane protein with amine oxidase activity, which is constitutively expressed on adipocytes and smooth muscle cells, as well as on ECs in lymph nodes, the gastrointestinal tract and the liver vasculature [29,33]. Described ligands are Siglec-9 (on granulocytes and monocytes) and Siglec-10 (on B lymphocytes, monocytes and eosinophils) ( Table 2) [124]. In biopsies of patients with PBC, PSC or alcoholic liver disease, VAP-1 levels were increased on ECs and myofibroblasts but VAP-1 was absent on cholangiocytes and hepatocytes.…”

“…Under normal conditions, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), which binds to α4β1, α4β7 and L-selectin (Table 2), is expressed almost exclusively on vascular ECs in the gastrointestinal tract and on ECs of the gut-associated lymphoid tissue [124]. However, in inflammatory liver diseases, MAdCAM-1 expression is induced on vascular ECs in the portal tract and is more prominent in livers of patients with PSC and AIH than in livers of patients with PBC or HCV infection [5,124,173]. Similar to other CAMs, MAdCAM-1 levels are upregulated in the presence of TNFα and IL-1β.…”