Senescent cell clearance by the immune system: Emerging therapeutic opportunities.
Senescent cell clearance by the immune system: Emerging therapeutic opportunities.
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DOI：
10.1016/j.smim.2019.04.003
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发表时间：
2018-12-01
影响因子：
7.8
通讯作者：
Kirkland, James L
中科院分区：
文献类型：
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作者：
Prata, Larissa G P Langhi;Ovsyannikova, Inna G;Kirkland, James L
由于炎症、代谢、DNA损伤或组织损伤信号，衰老细胞(SCs)起源于多个器官中的正常细胞。作为衰老相关分泌表型(SASP)的一部分，干细胞是一种非增殖但具有代谢活性的细胞，可以分泌一系列促炎和蛋白分解因子。衰老细胞抗凋亡通路(SCAP)保护SCs免受自身促凋亡SASP的影响。SCS可以化学吸引免疫细胞，通常被这些免疫细胞清除。在衰老和多种慢性病中，干细胞可以在功能失调的组织中积聚。SCS可以阻碍先天和获得性免疫反应。免疫系统清除SCs的能力丧失是否会促进免疫系统功能障碍，或者免疫功能障碍是否允许SC聚集，这些都是尚未完全解决的重要问题。SCS可能呈现不同的状态，与免疫细胞发生不同的相互作用，从而促进或抑制SC的清除，建立一个长期的促衰老和促炎环境，导致SASP被SASP招募和激活的免疫细胞调节。加强免疫细胞介导的干细胞清除的治疗方法可以为减轻干细胞负担提供杠杆。这种疗法可以包括疫苗、小分子免疫调节剂或其他方法。感觉剂是一种通过短暂地使SCAP失效来选择性地消除SCs的药物，可能被证明可以缓解老年人的免疫功能障碍，从而加速免疫介导的SCs的清除。对干细胞和免疫系统之间的相互作用了解得越多，就可能越快地开发出新的干预措施来延迟、预防或治疗与年龄相关的功能障碍以及与多种衰老相关的慢性疾病和紊乱。
Senescent cells (SCs) arise from normal cells in multiple organs due to inflammatory, metabolic, DNA damage, or tissue damage signals. SCs are non-proliferating but metabolically active cells that can secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype (SASP). Senescent cell anti-apoptotic pathways (SCAPs) protect SCs from their own pro-apoptotic SASP. SCs can chemo-attract immune cells and are usually cleared by these immune cells. During aging and in multiple chronic diseases, SCs can accumulate in dysfunctional tissues. SCs can impede innate and adaptive immune responses. Whether immune system loss of capacity to clear SCs promotes immune system dysfunction, or conversely whether immune dysfunction permits SC accumulation, are important issues that are not yet fully resolved. SCs may be able to assume distinct states that interact differentially with immune cells, thereby promoting or inhibiting SC clearance, establishing a chronically pro-senescent and pro-inflammatory environment, leading to modulation of the SASP by the immune cells recruited and activated by the SASP. Therapies that enhance immune cell-mediated clearance of SCs could provide a lever for reducing SC burden. Such therapies could include vaccines, small molecule immunomodulators, or other approaches. Senolytics, drugs that selectively eliminate SCs by transiently disabling their SCAPs, may prove to alleviate immune dysfunction in older individuals and thereby accelerate immune-mediated clearance of SCs. The more that can be understood about the interplay between SCs and the immune system, the faster new interventions may be developed to delay, prevent, or treat age-related dysfunction and the multiple senescence-associated chronic diseases and disorders.