Aging-associated dysregulation of homeostatic immune response termination (and not initiation).
Aging-associated dysregulation of homeostatic immune response termination (and not initiation).
复制标题
与衰老相关的稳态免疫反应终止（而不是启动）的失调。
DOI：
10.1111/acel.12589
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发表时间：
2017
期刊：
影响因子：
7.8
通讯作者：
Ucker,DavidS
中科院分区：
文献类型：
--
作者：
Pattabiraman,Goutham;Palasiewicz,Karol;Galvin,JohnP;Ucker,DavidS
免疫衰老是一种免疫反应不平衡的状态，其特征是与衰老相关的免疫各方面出现看似谨慎且矛盾的多种变化。我们询问凋亡细胞引发免疫调节反应（先天性凋亡免疫；IAI）的能力或 IAI 反应本身的衰老相关变化是否可能是与衰老相关的免疫衰老异常的基础。我们通过检查小鼠巨噬细胞在单细胞水平上的反应性作为动物年龄的函数来探讨这个问题。我们通过细胞荧光法监测促炎和抗炎细胞因子的表达，以响应促炎 Toll 样受体 (TLR) 刺激和凋亡细胞的抗炎治疗。虽然我们发现凋亡细胞的效力或 IAI 反应的启动和强度没有随年龄发生变化，但我们确实发现了与年龄和先前的免疫衰老表现相关的抗炎 IAI 反应终止的细胞内在缺陷。此外，我们发现 TLR 刺激后，与衰老相关的反应终止缺陷也很明显。这些令人惊讶的观察结果表明，随着动物年龄的增长，体内平衡免疫控制的丧失是由于反应终止（与反应启动不同）的失调造成的，并且影响到转录水平。我们认为，随着年龄的增长，细胞会陷入相对较长寿命的反应状态。衰老相关的免疫功能障碍可能反映了细胞免疫反应灵活性的降低。
Immunosenescence is a state of unbalanced immune responsiveness, characterized by a diverse repertoire of seemingly discreet and paradoxical alterations in all aspects of immunity arising in an aging‐associated manner. We asked whether aging‐associated alterations in the ability of apoptotic cells to elicit immunomodulatory responses (innate apoptotic immunity; IAI) or in IAI responses themselves might underlie the confounding aging‐associated anomalies of immunosenescence. We explored this question by examining, as a function of animal age, responsiveness of murine macrophages on the single cell level. We monitored the expression of pro‐ and anti‐inflammatory cytokines cytofluorimetrically in response to pro‐inflammatory Toll‐like receptor (TLR) stimulation and anti‐inflammatory treatment with apoptotic cells. While we found no alterations with age in the potency of apoptotic cells or in the initiation and magnitude of IAI responses, we did identify a cell‐intrinsic deficiency in anti‐inflammatory IAI response termination linked with age and preceding manifestations of immunosenescence. Further, we found that an aging‐associated deficiency in response termination also is evident following TLR stimulation. These surprising observations reveal that a loss of homeostatic immune control with animal age results from the dysregulation of response termination (as distinct from response initiation) and is exerted on the level of transcription. We suggest that, with advancing age, cells become locked into relatively longer‐lived response states. Aging‐associated immune dysfunctions may reflect a diminution in the cellular nimbleness of immune responsiveness.