PuSH - Publication Server of Helmholtz Zentrum München: Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.

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Yin, K. ; Patten, D.* ; Gough, S.C.* ; de Barros Gonçalves, S.* ; Chan, A.* ; Olan, I.* ; Cassidy, L.* ; Poblocka, M.* ; Zhu, H.* ; Lun, A.* ; Schuijs, M.J.* ; Young, A.* ; Martinez Jimenez, C.P. ; Halim, T.Y.F.* ; Shetty, S.* ; Narita, M.* ; Hoare, M.*

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

Genes Dev. 36, 533-549 (2022)

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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.

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