Partial Sleep Restriction Activates Immune Response-Related Gene Expression Pathways: Experimental and Epidemiological Studies in Humans

Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for five nights. The control subjects (N = 4) spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472). Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-κB signaling (PSTX16 correlated negatively with self-reported insufficient sleep in a population sample, while three other genes showed tendency for positive correlation. Of the ten most down-regulated genes, TBX21 and LGR6 correlated negatively and TGFBR3 positively with insufficient sleep. Partial sleep restriction affects the regulation of signaling pathways related to the immune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.

流行病学研究已证实，睡眠时间过短或睡眠不足与代谢性疾病及死亡风险升高显著相关。为阐明该关联背后的潜在机制，本研究旨在鉴定实验性诱导的部分睡眠限制所影响的基因与通路，并在人群层面验证其与睡眠不足的关联。
本实验设计模拟了工作日的睡眠限制方案：将9名健康男性的睡眠时间限制为每晚4小时，持续5晚；对照组4名受试者则每晚卧床8小时。
研究分别在基线期、睡眠限制结束后及恢复期采集受试者的白细胞RNA，通过全基因组微阵列（whole genome microarrays）进行全基因组表达分析，并辅以通路及转录因子分析。随后，将10个上调最显著与10个下调最显著的转录本的表达水平，与472名受试者组成的人群队列中，受试者对睡眠不足的主观评估结果进行相关性分析。
实验结果显示，部分睡眠限制改变了117个基因的表达水平。在上调最显著的25个转录本中，有8个与免疫功能相关；相应地，在上调最显著的25个基因本体（Gene Ontology, GO）通路中，亦有15个与免疫功能相关，包括B细胞活化、白细胞介素8生成及NF-κB信号通路（P<0.05）。在人群样本中，PSTX16的表达水平与自我报告的睡眠不足呈负相关，另有3个基因呈现出正相关的趋势。在下调最显著的10个基因中，TBX21与LGR6的表达水平与睡眠不足呈负相关，而TGFBR3则呈正相关。
本研究结果表明，部分睡眠限制会影响与免疫系统信号通路相关的调控过程；其中部分变化似乎具有长期性，这至少可以部分解释长期睡眠限制如何促发与炎症相关的病理状态，例如心脏代谢类疾病。