TY - JOUR
T1 - Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance
AU - Yin, Kelvin
AU - Patten, Daniel
AU - Gough, Sarah
AU - de Barros Gonçalves, Susana
AU - Chan, Adelyne
AU - Olan, Ioana
AU - Cassidy, Liam
AU - Poblocka, Marta
AU - Zhu, Haoran
AU - Lun, Aaron
AU - Schuijs, Martijn
AU - Young, Andrew
AU - Martinez-Jimenez, Celia
AU - Halim, Timotheus Y F
AU - Shetty, Shishir
AU - Narita, Masashi
AU - Hoare, Matthew
N1 - © 2022 Yin et al.; Published by Cold Spring Harbor Laboratory Press.
PY - 2022/5/26
Y1 - 2022/5/26
N2 - 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.
AB - 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.
KW - Animals
KW - Cellular Senescence/genetics
KW - Endothelial Cells/metabolism
KW - Endothelium/metabolism
KW - Mice
KW - NF-kappa B/metabolism
KW - Phenotype
U2 - 10.1101/gad.349585.122
DO - 10.1101/gad.349585.122
M3 - Article
C2 - 35618311
SN - 0890-9369
VL - 36
SP - 533
EP - 549
JO - Genes & Development
JF - Genes & Development
IS - 9-10
ER -