Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Program in Biomedical Sciences, University of Michigan, Ann Arbor, MI, United States; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States.
Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States.
Brain Behav Immun. 2015 Aug;48:244-57. doi: 10.1016/j.bbi.2015.03.014. Epub 2015 Apr 4.
Interactions between sleep and immune function are bidirectional. Although the mechanisms that govern these interactions are not fully elucidated, the pro-inflammatory cytokine, interleukin-1β (IL-1), is a known regulator of sleep and mediator of immune responses. To further clarify the underlying substrates of sleep and immune interactions, we engineered two transgenic mouse lines that express interleukin-1 receptor 1 (IL1R1) only in the central nervous system (CNS) and selectively on neurons (NSE-IL1R1) or astrocytes (GFAP-IL1R1). During spontaneous sleep, compared to wild type (WT) animals, NSE-IL1R1 and GFAP-IL1R1 mice have more rapid eye movement sleep (REMS) that is characterized by reduced theta power in the electroencephalogram (EEG) spectra. The non-REM sleep (NREMS) EEG of each of the IL1R1 transgenic mouse strains also is characterized by enhanced power in the delta frequency band. In response to 6h of sleep deprivation, sleep of both IL1R1 transgenic mouse strains is more consolidated than that of WT animals. Additionally, the NREMS EEG of NSE-IL1R1 mice contains less delta power after sleep deprivation, suggesting astroglial IL1R1 activity may modulate sleep homeostasis. Intracerebroventricular injection of IL-1 fails to alter sleep or brain temperature of NSE-IL1R1 or GFAP-IL1R1 mice. These data suggest that selective IL1R1 expression on neurons or on astrocytes is not sufficient for centrally-administered IL-1 to induce sleep or fever. Lack of sleep and febrile responses to IL-1 in these IL1R1 transgenic mouse strains may be due to their inability to produce IL-6 in brain. Overall, these studies demonstrate, through the use of novel transgenic mice, that IL1R1 on neurons and astrocytes differentially mediates aspects of sleep under physiological conditions and in response to central IL-1 administration.
睡眠和免疫功能之间的相互作用是双向的。虽然调节这些相互作用的机制尚未完全阐明，但促炎细胞因子白细胞介素-1β（IL-1）是睡眠的已知调节剂，也是免疫反应的介质。为了进一步阐明睡眠和免疫相互作用的潜在基质，我们构建了两种转基因小鼠品系，仅在中枢神经系统（CNS）中表达白细胞介素-1受体 1（IL1R1），并选择性地在神经元（NSE-IL1R1）或星形胶质细胞（GFAP-IL1R1）上表达。在自发睡眠期间，与野生型（WT）动物相比，NSE-IL1R1 和 GFAP-IL1R1 小鼠的快速眼动睡眠（REMS）更快，其特征是脑电图（EEG）频谱中的θ功率降低。每种 IL1R1 转基因小鼠品系的非快速眼动睡眠（NREMS）EEG 也以δ频带的功率增强为特征。在 6 小时的睡眠剥夺后，两种 IL1R1 转基因小鼠品系的睡眠都比 WT 动物更巩固。此外，NSE-IL1R1 小鼠的 NREMS EEG 在睡眠剥夺后含有较少的δ功率，这表明星形胶质细胞 IL1R1 活性可能调节睡眠稳态。脑室内注射 IL-1 不能改变 NSE-IL1R1 或 GFAP-IL1R1 小鼠的睡眠或脑温。这些数据表明，神经元或星形胶质细胞上选择性的 IL1R1 表达不足以使中枢给予的 IL-1 诱导睡眠或发热。这些 IL1R1 转基因小鼠品系对 IL-1 缺乏睡眠和发热反应可能是由于它们不能在脑中产生 IL-6。总的来说，这些研究通过使用新型转基因小鼠表明，神经元和星形胶质细胞上的 IL1R1 不同程度地调节生理条件下的睡眠以及对中枢 IL-1 给药的反应。
