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.

中文翻译：

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衰老诱导的内皮表型支持免疫介导的衰老监测

衰老是一种应激反应性肿瘤抑制机制，与衰老相关分泌表型 (SASP) 的表达相关。通过 SASP，衰老细胞触发自身免疫介导的消除，如果逃避则会导致肿瘤发生。衰老的实质细胞通过内皮与循环免疫细胞分离，内皮是微环境信号传导的目标。在这里，我们显示 SASP 诱导内皮细胞 NF-κB 活性以及 SASP 诱导的典型 NF-κB 成分Rela 的内皮表达支持衰老监测。使用人肝窦内皮细胞 (LSEC)，我们表明 SASP 诱导的内皮 NF-κB 活性调节支持免疫细胞募集的保守转录程序。此外，致癌性肝细胞衰老在体内驱动小鼠 LSEC NF-κB 活性。至关重要的是，我们在衰老监测中展示了两种不同的内皮通路。首先， Rela的内皮特异性缺失会阻止表达 Stat1 的 CD4 ⁺ T 淋巴细胞的发育。其次，SASP 上调 LSEC 上的 ICOSLG，ICOS-ICOSLG 轴有助于清除衰老细胞。我们的研究结果表明，内皮细胞是一个非自主的 SASP 靶标，也是免疫介导的衰老监测的组织中心。