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

doi:10.1016/j.isci.2023.107966

The senescent secretome drives PLVAP expression in cultured human hepatic endothelial cells to promote monocyte transmigration

iScience. 2023 Sep 19;26(10):107966. doi: 10.1016/j.isci.2023.107966. eCollection 2023 Oct 20.

Authors

Alex L Wilkinson¹, Samuel Hulme¹, James I Kennedy¹, Emily R Mann¹, Paul Horn¹, Emma L Shepherd², Kelvin Yin³, Marco Y W Zaki⁴, Gareth Hardisty⁵, Wei-Yu Lu⁵, Pia Rantakari^{6

7}, David H Adams¹, Marko Salmi^{6

7}, Matthew Hoare^{3

8}, Daniel A Patten^{1

9}, Shishir Shetty^{1

9}

Affiliations

¹ Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
² College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK.
³ University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.
⁴ Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt.
⁵ Centre for Inflammation Research, University of Edinburgh, Edinburgh EH8 9YL, UK.
⁶ Institute of Biomedicine, University of Turku, Turku, Finland.
⁷ MediCity Research Laboratory, University of Turku, Turku, Finland.
⁸ University of Cambridge, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
⁹ National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Abstract

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.

Keywords: Cell biology; Microenvironment; Molecular biology; Omics; Transcriptomics.

Abstract

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