Cellular senescence: from growth arrest to immunogenic conversion
Cellular senescence: from growth arrest to immunogenic conversion
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DOI：
10.1007/s11357-015-9764-2
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发表时间：
2015-04-01
期刊：
影响因子：
--
通讯作者：
Faragher, R. G. A.
中科院分区：
文献类型：
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作者：
Burton, D. G. A.;Faragher, R. G. A.
细胞衰老首先在人成纤维细胞中报道为延长培养后稳定的体外生长停滞状态。从最初的观察开始，各种其他表型特征已被证明与衰老成纤维细胞中不可逆的细胞周期退出相关。这些包括（1）促炎分泌反应，（2）免疫配体的上调，（3）对凋亡刺激的改变的反应和（4）混杂基因表达（可能由于染色质重塑导致的基因的随机激活）。与衰老成纤维细胞相关的许多特征似乎促进转化为免疫原性表型，其促进免疫系统的自我消除。促炎细胞因子可以吸引和激活免疫细胞，膜结合的免疫配体的呈递允许特异性识别，并且混杂基因表达可以起作用以产生一系列组织限制性蛋白质，其随后可以被加工成肽以通过MHC分子呈递。然而，来自不同组织和物种的衰老细胞的表型通常被认为与衰老的人成纤维细胞中所见的表型大致相似，但数据显示了一个更复杂的画面，其中生长停滞机制，组织来源和物种都可以从根本上调节这种基本模式。此外，细胞衰老的既定触发因素通常与DNA损伤反应（DDR）相关，但这可能不是衰老细胞的普遍特征。因此，我们讨论了DNA损伤在调节衰老细胞的免疫原性反应中的作用，此外还讨论了可能独立于DNA损伤而发生的不太确定的Batypical衰老状态。
Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a proinflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, wellestablished triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established Batypical senescent states that may occur independent of DNA damage.