Investigating the role of MR and PLVAP in hepatic leukocyte recruitment during chronic liver inflammation

Wilkinson, Alex Louise (2023). Investigating the role of MR and PLVAP in hepatic leukocyte recruitment during chronic liver inflammation. University of Birmingham. Ph.D.

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Abstract

Chronic liver diseases (CLDs) are characterised by inflammation and fibrosis which are driven by aberrant leukocyte recruitment. This process is mediated by specialised discontinuous endothelia, known as hepatic sinusoidal endothelial cells (HSEC), which act as the liver gatekeepers. During chronic inflammation, HSEC undergo substantial phenotypic changes, including upregulation of adhesion molecules, further driving leukocyte recruitment and exacerbating inflammation. The composition of the hepatic immune microenvironment determines the outcome of liver injury and understanding the mechanisms which regulate this process is critical to identify novel therapeutic targets. Mannose receptor (MR) and plasmalemma vesicle-associated protein (PLVAP) have previously been implicated in immune cell trafficking but their contribution to hepatic leukocyte recruitment remains undefined. This study aimed to characterise the expression of MR and PLVAP in normal and diseased human liver, understand their regulation in the hepatic sinusoids, and investigate their potential role in hepatic leukocyte recruitment. Immunohistochemistry and gene expression studies demonstrated that MR and PLVAP are differentially expressed in liver endothelium, with MR being downregulated and PLVAP being upregulated, in CLD and hepatocellular carcinoma. MR was resistant to regulation in primary human HSEC and did not seem to be involved in lymphocyte recruitment. In contrast, PLVAP was upregulated by several soluble factors, most notably by the senescence-associated secretory phenotype (SASP). The SASP, comprised of several cytokines and chemokines, is known to facilitate senescence surveillance by stimulating leukocyte recruitment. Additional experiments using patient tissue samples uncovered a previously unreported link between hepatic senescence, immune cell infiltration, and PLVAP expression in CLD. Furthermore, in vitro flow adhesion assays showed that PLVAP plays a selective functional role in monocyte paracellular transmigration, whilst having no impact on lymphocyte recruitment. These findings suggest that senescent cell-endothelial crosstalk drives PLVAP expression and shapes the immune landscape in chronic liver inflammation.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):