Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice
Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice
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DOI：
10.1038/s41598-020-59541-y
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发表时间：
2020-02-13
影响因子：
4.6
通讯作者：
Yagita, Kazuhiro
中科院分区：
文献类型：
--
作者：
Inokawa, Hitoshi;Umemura, Yasuhiro;Yagita, Kazuhiro
现代社会以24/7的生活方式为特征，导致环境周期和内源性昼夜节律之间的失调。持续的昼夜节律失调导致对健康和健康寿命的有害影响。然而，其潜在机制仍未完全了解。在这里，我们将成年野生型小鼠置于不同的慢性时差模式下，结果表明，长期的昼夜节律失调导致了显著的早期死亡。使用肝脏和肾脏进行的无偏见RNA测序分析显示，在这两个器官中，与免疫系统和免疫疾病相关的基因调控途径被显著激活。与此一致，我们观察到脂肪性肝炎伴炎症细胞浸润。对脾脏和肠系膜淋巴结衰老相关免疫细胞亚群的研究显示，PD-1(+)CD44（高）CD4 T细胞和CD95(+)GL7（+）生发中心B细胞的增加，表明长期的昼夜节律失调加剧了免疫衰老和随之而来的慢性炎症。我们的研究结果强调免疫稳态是对抗生物钟相关疾病的关键干预靶点。
Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, we observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1(+)CD44(high) CD4 T cells as well as CD95(+)GL7(+) germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.