PDF(Pubmed)
Abstract：
The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.
摘要：
衰老细胞的积累促进衰老和与年龄有关的疾病，但是衰老细胞用来逃避免疫清除并在组织中积累的分子机制仍有待阐明。在这里，我们报道了p16阳性衰老细胞上调免疫检查点蛋白程序性死亡配体1（PD-L1）在衰老和慢性炎症中积累。我们显示p16介导的细胞周期激酶CDK4/6抑制通过下调其泛素依赖性降解诱导衰老细胞中的PD-L1稳定性。表达p16的衰老肺泡巨噬细胞会升高PD-L1，从而促进免疫抑制环境，从而增加衰老细胞的负担。用激活效应细胞上的Fcγ受体的抗PD-L1抗体处理导致PD-L1和p16阳性细胞的消除。我们的研究揭示了衰老细胞中p16依赖性调节PD-L1蛋白稳定性的分子机制，并揭示了靶向PD-L1改善衰老细胞免疫监视和改善衰老相关炎症的潜力。
