Regulation of plasma histamine levels by the mast cell clock and its modulation by stress.
Regulation of plasma histamine levels by the mast cell clock and its modulation by stress.
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DOI：
10.1038/srep39934
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发表时间：
2017-01-11
影响因子：
4.6
通讯作者：
Nakao A
中科院分区：
文献类型：
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作者：
Nakamura Y;Ishimaru K;Shibata S;Nakao A
在稳态下，血浆组胺水平表现出昼夜变化，夜间峰值，这与夜间过敏症状的加重有关。然而，监管机制在很大程度上尚未探索。这项研究确定了稳态血浆组胺水平是如何调节和环境因素的影响。我们发现，血浆组胺水平降低肥大细胞缺陷小鼠和他们的昼夜变化丢失在肥大细胞缺陷小鼠与骨髓来源的肥大细胞（BMMCs），窝藏突变的昼夜节律基因时钟重建。生物钟在时间上调节肥大细胞中参与组胺转运的有机阳离子转运蛋白3（OCT 3）的表达; OCT抑制消除了血浆组胺水平的昼夜变化。在异常光/暗条件下饲养或遭受束缚应激的小鼠表现出肥大细胞时钟的去同步化，伴随着OCT 3表达和血浆组胺水平的昼夜变化的丧失。小鼠中化合物48/80诱导的血浆外渗的程度与血浆组胺水平相关。总的来说，肥大细胞时钟介导稳态血浆组胺水平的昼夜节律调节，部分通过控制OCT 3表达，这可以通过应激调节。此外，我们认为血浆组胺水平增强肥大细胞介导的过敏反应。
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.