The senescent secretome drives PLVAP expression in cultured human hepatic endothelial cells to promote monocyte transmigration
Alex L. Wilkinson,
Samuel Hulme,
James I. Kennedy,
Emily R. Mann,
Paul Horn,
Emma L. Shepherd,
Kelvin Yin,
Marco Y.W. Zaki,
Gareth Hardisty,
Wei-Yu Lu,
Pia Rantakari,
David H. Adams,
Marko Salmi,
Matthew Hoare,
Daniel A. Patten,
Shishir Shetty
Affiliations
Alex L. Wilkinson
Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
Samuel Hulme
Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
James I. Kennedy
Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
Emily R. Mann
Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
Paul Horn
Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
Emma L. Shepherd
College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
Kelvin Yin
University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK
Marco Y.W. Zaki
Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt
Gareth Hardisty
Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9YL, UK
Wei-Yu Lu
Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9YL, UK
Pia Rantakari
Institute of Biomedicine, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland
David H. Adams
Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
Marko Salmi
Institute of Biomedicine, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland
Matthew Hoare
University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK; University of Cambridge, Department of Medicine, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
Daniel A. Patten
Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
Shishir Shetty
Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Corresponding author
Summary: 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.
