Medical Research Center and Department of Laboratory Medicine, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan, China.
Guangdong Keyway Testing Technology Co, Ltd., Foshan, China.
J Cell Mol Med. 2020 Dec;24(24):14583-14595. doi: 10.1111/jcmm.16088. Epub 2020 Nov 13.
Long-term subjection to shift work increases the risk of cancer. The purpose of the present study was to explore the mechanism by which chronic circadian disruption impairs natural killer (NK) cell immunosurveillance. Mice were subjected to light-dark reverse every 4 days for 12 weeks to disrupt normal circadian rhythm. NK cell development and function were evaluated by flow cytometry. The mRNA and protein levels of period 1 (per1) and per2 were suppressed, while circadian locomotor output cycle kaput (CLOCK) was increased in the shifted mice, indicating successful generation of the circadian rhythm disruption mouse model. Chronic shift-lag promoted NK cell ageing, which is likely due to the reduction in Ly49 family receptor expression in shifted NK. We further studied the effects of circadian rhythm disruption on NK cell function. Chronic shift-lag inhibited NK cell secretion of granular CD107a and interferon gamma. Moreover, chronic shift-lag attenuated the clearance of MHC-I-deficient tumour cells by NK cells in vivo and promoted lung metastasis of B16F10 melanomas. Furthermore, chronic shift-lag reduced NK cell killing function, which may be due to the suppression of Eomes transcription factor expression, which inhibiting the transcription of CD122. In conclusion, our findings suggest that chronic circadian disruption attenuates NK cell cytolytic activity by decreasing the expression of CD122.
长期轮班工作会增加患癌症的风险。本研究旨在探讨慢性生物钟紊乱破坏自然杀伤 (NK) 细胞免疫监视的机制。将小鼠每隔 4 天进行一次明暗颠倒处理，持续 12 周，以破坏正常的生物钟节律。通过流式细胞术评估 NK 细胞的发育和功能。结果表明，在移位小鼠中，周期 1 (per1) 和 per2 的 mRNA 和蛋白水平降低，而昼夜节律运动输出周期 kaput (CLOCK) 增加，表明成功建立了生物钟紊乱小鼠模型。慢性移相滞后促进 NK 细胞衰老，这可能是由于移位 NK 中 Ly49 家族受体表达减少所致。我们进一步研究了生物钟紊乱对 NK 细胞功能的影响。慢性移相滞后抑制 NK 细胞颗粒 CD107a 和干扰素 γ的分泌。此外，慢性移相滞后减弱了 NK 细胞在体内清除 MHC-I 缺陷肿瘤细胞的能力，并促进了 B16F10 黑色素瘤的肺转移。此外，慢性移相滞后降低了 NK 细胞的杀伤功能，这可能是由于 Eomes 转录因子表达的抑制，从而抑制了 CD122 的转录。综上所述，我们的研究结果表明，慢性生物钟紊乱通过降低 CD122 的表达来减弱 NK 细胞的细胞溶解活性。
