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Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Gough, Sarah 
de Barros Gonçalves, Susana 

Abstract

Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS-ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.

Description

Keywords

Journal Title

Genes Dev

Conference Name

Journal ISSN

0890-9369
1549-5477

Volume Title

Publisher

Cold Spring Harbor Laboratory
Sponsorship
Cancer Research UK (CB4210)
Cancer Research UK (19924)
Medical Research Council (MR/R010013/1)
Cancer Research UK (via Newcastle University) (BH183441)
Cancer Research UK (via Newcastle University) (BH172934)
Cancer Research UK (C52489/A29681)
Cancer Research UK (A19924)
Biotechnology and Biological Sciences Research Council (BB/S013466/1)
BBSRC (BB/T013486/1)
National Institute for Health Research (NIHRDH-IS-BRC-1215-20014)