A1 Refereed original research article in a scientific journal
The senescent secretome drives PLVAP expression in cultured human hepatic endothelial cells to promote monocyte transmigration
Authors: Wilkinson AL, Hulme S, Kennedy JI, Mann ER, Horn P, Shepherd EL, Yin K, Zaki MYW, Hardisty G, Lu WY, Rantakari Pia, Adams DH, Salmi Marko, Hoare M, Patten DA, Shetty S
Publisher: Cell Press
Publication year: 2023
Journal: iScience
Journal name in source: iScience
Journal acronym: iScience
Article number: 107966
Volume: 26
Issue: 10
ISSN: 2589-0042
eISSN: 2589-0042
DOI: https://doi.org/10.1016/j.isci.2023.107966
Web address : https://doi.org/10.1016/j.isci.2023.107966
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/181475876
Liver sinusoidal endothelial cells (LSEC) undergo significant phenotypic change in chronic liver disease (CLD), and yet the factors that drive this process and the impact on their function as a vascular barrier and gatekeeper for immune cell recruitment are poorly understood. Plasmalemma-vesicle-associated protein (PLVAP) has been characterized as a marker of LSEC in CLD; notably we found that PLVAP upregulation strongly correlated with markers of tissue senescence. Furthermore, exposure of human LSEC to the senescence-associated secretory phenotype (SASP) led to a significant upregulation of PLVAP. Flow-based assays demonstrated that SASP-driven leukocyte recruitment was characterized by paracellular transmigration of monocytes while the majority of lymphocytes migrated transcellularly. Knockdown studies confirmed that PLVAP selectively supported monocyte transmigration mediated through PLVAP's impact on LSEC permeability by regulating phospho-VE-cadherin expression and endothelial gap formation. PLVAP may therefore represent an endothelial target that selectively shapes the senescence-mediated immune microenvironment in liver disease.
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