Department of Immunology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, 2-2, Wakamatsu-cho, Shinjuku-ku, Tokyo, 162-8480, Japan.
Sci Rep. 2017 Jan 11;7:39934. doi: 10.1038/srep39934.
At steady state, plasma histamine levels exhibit circadian variations with nocturnal peaks, which is implicated in the nighttime exacerbation of allergic symptoms. However, the regulatory mechanisms are largely unexplored. This study determined how steady-state plasma histamine levels are regulated and affected by environmental factors. We found that plasma histamine levels decreased in mast cell-deficient mice and their circadian variations were lost in mast cell-deficient mice reconstituted with bone marrow-derived mast cells (BMMCs) harboring a mutation in the circadian gene Clock. Clock temporally regulates expression of organic cation transporter 3 (OCT3), which is involved in histamine transport, in mast cells; OCT inhibition abolished circadian variations in plasma histamine levels. Mice housed under aberrant light/dark conditions or suffering from restraint stress exhibited de-synchronization of the mast cell clockwork, concomitant with the loss of circadian variations in OCT3 expression and plasma histamine levels. The degree of compound 48/80-induced plasma extravasation in mice was correlated with plasma histamine levels. Collectively, the mast cell clock mediates circadian regulation of plasma histamine levels at steady state, in part by controlling OCT3 expression, which can be modulated by stress. Additionally, we propose that plasma histamine levels potentiate mast cell-mediated allergic reactions.
在稳态下，血浆组胺水平表现出昼夜节律变化，夜间峰值升高，这与过敏症状在夜间加重有关。然而，其调节机制在很大程度上尚未被探索。本研究旨在确定稳态血浆组胺水平是如何被调节的，并受环境因素的影响。我们发现，在肥大细胞缺陷小鼠中，血浆组胺水平下降，并且在骨髓来源的肥大细胞（BMMC）中重建的肥大细胞缺陷小鼠中，其昼夜节律变化消失，这些 BMMC 携带昼夜节律基因 Clock 的突变。Clock 时间上调节参与组胺转运的有机阳离子转运体 3（OCT3）的表达；OCT 抑制消除了血浆组胺水平的昼夜节律变化。在异常的明暗条件下饲养或遭受束缚应激的小鼠表现出肥大细胞生物钟的去同步化，同时 OCT3 表达和血浆组胺水平的昼夜节律变化消失。在小鼠中，化合物 48/80 诱导的血浆渗出程度与血浆组胺水平相关。总之，肥大细胞生物钟介导稳态下血浆组胺水平的昼夜调节，部分通过控制 OCT3 表达来实现，而应激可以调节 OCT3 表达。此外，我们提出血浆组胺水平增强了肥大细胞介导的过敏反应。
