Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine, Guangzhou, China.
Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China.
J Allergy Clin Immunol. 2024 Sep;154(3):707-718. doi: 10.1016/j.jaci.2024.04.024. Epub 2024 May 9.
While the daily rhythm of allergic rhinitis (AR) has long been recognized, the molecular mechanism underlying this phenomenon remains enigmatic.
We aimed to investigate the role of circadian clock in AR development and to clarify the mechanism by which the daily rhythm of AR is generated.
AR was induced in mice with ovalbumin. Toluidine blue staining, liquid chromatography-tandem mass spectrometry analysis, real-time quantitative PCR, and immunoblotting were performed with AR and control mice.
Ovalbumin-induced AR is diurnally rhythmic and associated with clock gene disruption in nasal mucosa. In particular, Rev-erbα is generally downregulated and its rhythm retained, but with a near-12-hour phase shift. Furthermore, global knockout of core clock gene Bmal1 or Rev-erbα increases the susceptibility of mice to AR and blunts AR rhythmicity. Importantly, nasal solitary chemosensory cells (SCCs) are rhythmically activated, and inhibition of the SCC pathway leads to attenuated AR and a loss of its rhythm. Moreover, rhythmic activation of SCCs is accounted for by diurnal expression of ChAT (an enzyme responsible for the synthesis of acetylcholine) and temporal generation of the neurotransmitter acetylcholine. Mechanistically, Rev-erbα trans-represses Chat through direct binding to a specific response element, generating a diurnal oscillation in this target gene.
SCCs, under the control of Rev-erbα, are a driver of AR rhythmicity; targeting SCCs should be considered as a new avenue for AR management.
虽然过敏性鼻炎 (AR) 的日常节律早已被人们所认识，但这种现象背后的分子机制仍不清楚。
我们旨在研究生物钟在 AR 发展中的作用，并阐明 AR 日常节律产生的机制。
使用卵清蛋白诱导 AR 模型，对 AR 小鼠和对照组小鼠进行甲苯胺蓝染色、液相色谱-串联质谱分析、实时定量 PCR 和免疫印迹分析。
卵清蛋白诱导的 AR 呈昼夜节律性，与鼻黏膜中时钟基因的破坏有关。特别是，Rev-erbα 普遍下调但其节律保留，但相位几乎延迟了 12 小时。此外，核心时钟基因 Bmal1 或 Rev-erbα 的全身性敲除会增加小鼠对 AR 的易感性，并使 AR 的节律性减弱。重要的是，鼻单一化学感觉细胞 (SCC) 呈节律性激活，而抑制 SCC 途径会导致 AR 减弱且其节律丧失。此外，SCC 的节律性激活归因于 ChAT（负责合成乙酰胆碱的酶）的昼夜表达和神经递质乙酰胆碱的时间生成。从机制上讲，Rev-erbα 通过直接结合特定的反应元件来反式抑制 Chat，从而使该靶基因产生昼夜振荡。
SCCs 在 Rev-erbα 的控制下是 AR 节律性的驱动因素；针对 SCCs 应该被视为 AR 管理的新途径。
