Schloss Maximilian J, Hilby Michael, Nitz Katrin, Guillamat Prats Raquel, Ferraro Bartolo, Leoni Giovanna, Soehnlein Oliver, Kessler Thorsten, He Wenyan, Luckow Bruno, Horckmans Michael, Weber Christian, Duchene Johan, Steffens Sabine
From the Institute for Cardiovascular Prevention (IPEK) (M.J.S., M. Hilby, K.N., R.G.P., B.F., G.L., O.S., M. Horckmans, C.W., J.D., S.S.), and BioMedical Center, Walter-Brendel-Centre for Experimental Medicine (W.H.), Ludwig-Maximilians-University (LMU), Munich, Germany; Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (K.N.); German Heart Center Munich, Technical University Munich (TUM), Germany (T.K.); Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Arbeitsgruppe Klinische Biochemie, Germany (B.L.); German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Germany (O.S., C.W., S.S.); Department of Physiology and Pharmacology (FyFa), Karolinska Institutet, Stockholm, Sweden (O.S.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands (C.W.).
Arterioscler Thromb Vasc Biol. 2017 Sep;37(9):1640-1645. doi: 10.1161/ATVBAHA.117.309259. Epub 2017 Jun 29.
Circadian regulation of neutrophil homeostasis affects myocardial infarction (MI) healing. It is unknown whether diurnal variations of monocyte counts exist in the heart and whether this affects their cardiac infiltration in response to MI.
Murine blood and organs were harvested at distinct times of day and analyzed by flow cytometry. Ly6C monocyte surface expression levels of chemokine receptors (CCR) were ≈2-fold higher at the beginning of the active phase, Zeitgeber Time (ZT) 13 compared with ZT5. This was because of enhanced receptor surface expression at ZT13, whereas no significant changes in total cellular protein levels were found. Most blood Ly6C monocytes were CCR2, whereas only a minority was CCR1 and CCR5. We also found diurnal changes of classical monocyte blood counts in humans, being higher in the evening, while exhibiting enhanced CCR2 surface expression in the morning. In support of monocyte oscillations between blood and tissue, murine cardiac Ly6C monocyte counts were highest at ZT13, accompanied by an upregulation of cardiac CC chemokine ligand 2 mRNA. Mice subjected to MI at ZT13 had an even higher upregulation of CCR2 surface expression on circulating monocytes compared with noninfarcted mice and more elevated cardiac CC chemokine ligand 2 protein expression and more pronounced Ly6C monocyte infiltration compared with ZT5-infarcted mice. Concomitantly, CCR2 antagonism only inhibited the excessive cardiac Ly6C monocyte infiltration after ZT13 MI but not ZT5 MI.
CCR2 surface expression on Ly6C monocytes changes in a time-of-day-dependent manner, which crucially affects cardiac monocyte recruitment after an acute ischemic event.
中性粒细胞稳态的昼夜节律调节影响心肌梗死（MI）的愈合。目前尚不清楚心脏中单核细胞计数是否存在昼夜变化，以及这是否会影响它们对MI的心脏浸润。
在一天中的不同时间采集小鼠血液和器官，并通过流式细胞术进行分析。与 Zeitgeber 时间（ZT）5 相比，在活动期开始时（ZT13），趋化因子受体（CCR）的 Ly6C 单核细胞表面表达水平约高 2 倍。这是由于 ZT13 时受体表面表达增强，而细胞总蛋白水平未发现显著变化。大多数血液中的 Ly6C 单核细胞是 CCR2，而只有少数是 CCR1 和 CCR5。我们还发现人类经典单核细胞血液计数存在昼夜变化，晚上较高，而早上 CCR2 表面表达增强。为支持单核细胞在血液和组织之间的振荡，小鼠心脏 Ly6C 单核细胞计数在 ZT13 时最高，同时心脏 CC 趋化因子配体 2 mRNA 上调。与未梗死小鼠相比，在 ZT13 发生 MI 的小鼠循环单核细胞上 CCR2 表面表达的上调更为明显，与 ZT5 梗死的小鼠相比，心脏 CC 趋化因子配体 2 蛋白表达更高，Ly6C 单核细胞浸润更明显。同时，CCR2 拮抗仅抑制 ZT13 MI 后过度的心脏 Ly6C 单核细胞浸润，而不抑制 ZT5 MI。
Ly6C 单核细胞上 CCR2 表面表达以时间依赖的方式变化，这对急性缺血事件后心脏单核细胞募集至关重要。
