{"title":"免疫抑制性 PD-1/PD-L1 检查点通路在衰老过程和老年相关疾病中的作用","authors":"Antero Salminen","doi":"10.1007/s00109-024-02444-6","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Abstract</h3><p>The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8<sup>+</sup> T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8<sup>+</sup> T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy.</p><h3 data-test=\"abstract-sub-heading\">Key messages</h3>\n<ul>\n<li>\n<p>Senescent cells accumulate within tissues during aging and age-related diseases.</p>\n</li>\n<li>\n<p>Senescent cells are able to escape immune surveillance by cytotoxic immune cells.</p>\n</li>\n<li>\n<p>Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells.</p>\n</li>\n<li>\n<p>Age-related signaling stimulates the expression of PD-L1 protein in senescent cells.</p>\n</li>\n<li>\n<p>Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.</p>\n</li>\n</ul>","PeriodicalId":16341,"journal":{"name":"Journal of Molecular Medicine","volume":"4 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases\",\"authors\":\"Antero Salminen\",\"doi\":\"10.1007/s00109-024-02444-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3 data-test=\\\"abstract-sub-heading\\\">Abstract</h3><p>The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8<sup>+</sup> T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8<sup>+</sup> T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy.</p><h3 data-test=\\\"abstract-sub-heading\\\">Key messages</h3>\\n<ul>\\n<li>\\n<p>Senescent cells accumulate within tissues during aging and age-related diseases.</p>\\n</li>\\n<li>\\n<p>Senescent cells are able to escape immune surveillance by cytotoxic immune cells.</p>\\n</li>\\n<li>\\n<p>Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells.</p>\\n</li>\\n<li>\\n<p>Age-related signaling stimulates the expression of PD-L1 protein in senescent cells.</p>\\n</li>\\n<li>\\n<p>Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.</p>\\n</li>\\n</ul>\",\"PeriodicalId\":16341,\"journal\":{\"name\":\"Journal of Molecular Medicine\",\"volume\":\"4 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-04-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Molecular Medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1007/s00109-024-02444-6\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Molecular Medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1007/s00109-024-02444-6","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
摘要组织内衰老细胞的积累是衰老过程的标志。衰老细胞也普遍存在于许多与年龄有关的疾病和癌症微环境中。异常细胞逃脱免疫监视表明细胞毒性免疫细胞（如 CD8+ T 细胞和自然杀伤（NK）细胞）的功能存在缺陷。最近的研究发现，衰老细胞中程序性死亡配体 1（PD-L1）蛋白的表达量大量增加。PD-L1 蛋白数量的增加可保护衰老细胞不被细胞毒性免疫细胞中的 PD-1 检查点受体清除。事实上，PD-1 受体的激活会抑制 CD8+ T 细胞和 NK 细胞的细胞毒特性，从而促进免疫衰老状态。抑制性 PD-1/PD-L1 检查点通路与免疫抑制细胞合作发挥作用；例如，PD-1 受体的激活可促进调节性 T 细胞（Treg）、髓源性抑制细胞（MDSC）和 M2 巨噬细胞的分化，而免疫抑制细胞分泌的细胞因子会刺激免疫抑制 PD-L1 蛋白的表达。有趣的是，许多已知促进细胞衰老和老化过程的信号通路都是 PD-L1 蛋白表达的重要刺激因素，如表观遗传调控、炎症介质、mTOR 相关信号、cGAS-STING 通路和 AhR 信号。看来，抑制性 PD-1/PD-L1 免疫检查点轴在衰老细胞的积累过程中起着至关重要的作用，从而促进了组织的衰老过程。因此，阻断 PD-1/PD-L1 检查点信号转导可能是一种潜在的抗衰老溶解疗法。衰老细胞中程序性死亡配体 1（PD-L1）的表达明显增加，与年龄相关的信号刺激衰老细胞中 PD-L1 蛋白的表达。
The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases
Abstract
The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8+ T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8+ T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy.
Key messages
Senescent cells accumulate within tissues during aging and age-related diseases.
Senescent cells are able to escape immune surveillance by cytotoxic immune cells.
Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells.
Age-related signaling stimulates the expression of PD-L1 protein in senescent cells.
Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.
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