Aging disrupts circadian gene regulation and function in macrophages.
Aging disrupts circadian gene regulation and function in macrophages.
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DOI：
10.1038/s41590-021-01083-0
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发表时间：
2022-02
影响因子：
30.5
通讯作者：
Andreasson, Katrin I.
中科院分区：
文献类型：
--
作者：
Blacher, Eran;Tsai, Connie;Litichevskiy, Lev;Shipony, Zohar;Iweka, Chinyere Agbaegbu;Schneider, Kai Markus;Chuluun, Bayarsaikhan;Heller, H. Craig;Menon, Vilas;Thaiss, Christoph A.;Andreasson, Katrin I.
衰老的特点是更容易受到感染以及发生动脉粥样硬化、虚弱、癌症和神经退行性疾病等炎症性疾病。在这里，我们发现衰老与昼夜节律性先天免疫反应的丧失有关，包括单核细胞从骨髓到血液的运输、吞噬作用和对细菌感染的抵抗力。与年轻组织巨噬细胞相比，体内平衡免疫反应的下降与老年人昼夜节律基因转录的显着消失有关。与老年巨噬细胞相比，年轻巨噬细胞的染色质可及性明显更高，但这种差异并不能解释老年巨噬细胞中节律性基因转录的丧失。相反，Kruppel 样因子 4 (Klf4) 的昼夜表达在衰老的巨噬细胞中选择性减少，Klf4 是一种在调节细胞分化和重编程方面已确立的转录因子。此外，在衰老的巨噬细胞中，Klf4 与染色质的结合在与细胞重编程不同的结合基序上消失，这表明 Klf4 在维持关键的年轻节律性免疫反应中具有独特的作用。对携带 Klf4 基因变异的人类受试者进行的检查显示，其与年龄依赖性的细菌感染导致的死亡易感性相关。我们的结果表明，衰老巨噬细胞中节律性 Klf4 表达的丧失与昼夜节律稳态的破坏有关，这种机制可能是与年龄相关的保护性免疫反应丧失的基础。
Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases like atherosclerosis, frailty, cancer, and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, phagocytosis, and resistance to bacterial infection. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged as compared to young tissue macrophages. Chromatin accessibility was significantly greater in young versus aged macrophages, however this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like Factor 4 (Klf4), a transcription factor well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Moreover, Klf4 binding to chromatin was lost in aging macrophages at a binding motif distinct from that involved in cellular reprogramming, suggesting a distinct role of Klf4 in maintenance of critical youthful rhythmic immune responses. Examination in human subjects with genetic variants of Klf4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian homeostasis, and this mechanism may underlie age-associated loss of protective immune responses.
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昼夜节律时钟控制脓毒症中的免疫检查点通路
影响因子：
8.8
作者：
Deng W;Zhu S;Zeng L;Liu J;Kang R;Yang M;Cao L;Wang H;Billiar TR;Jiang J;Xie M;Tang D
通讯作者：
Tang D
影响因子：
30.5
作者：
Liu, Qingkun;Johnson, Emily M.;Andreasson, Katrin I.
通讯作者：
Andreasson, Katrin I.
DOI：
10.1084/jem.20111490
发表时间：
2011-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dykstra B;Olthof S;Schreuder J;Ritsema M;de Haan G
通讯作者：
de Haan G
影响因子：
3.5
作者：
Hughes ME;Hogenesch JB;Kornacker K
通讯作者：
Kornacker K
影响因子：
3.5
作者：
Hutchison, Alan L.;Allada, Ravi;Dinner, Aaron R.
通讯作者：
Dinner, Aaron R.