From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Circ Res. 2014 Jul 7;115(2):284-95. doi: 10.1161/CIRCRESAHA.115.303567. Epub 2014 May 1.
Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that, in several organs, tissue-resident macrophages may self-maintain through local proliferation.
Our aim was to study the contribution of monocytes to cardiac-resident macrophages in steady state, after macrophage depletion in CD11b(DTR/+) mice and in myocardial infarction.
Using in vivo fate mapping and flow cytometry, we estimated that during steady state the heart macrophage population turns over in ≈1 month. To explore the source of cardiac-resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3±3.4%, whereas heart macrophages showed a much lower chimerism of 2.7±0.5% (P<0.01). Macrophages self-renewed locally through proliferation: 2.1±0.3% incorporated bromodeoxyuridine 2 hours after a single injection, and 13.7±1.4% heart macrophages stained positive for the cell cycle marker Ki-67. The cells likely participate in defense against infection, because we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue-resident macrophages died locally, whereas some also migrated to hematopoietic organs. If the steady state was perturbed by coronary ligation or diphtheria toxin-induced macrophage depletion in CD11b(DTR/+) mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation.
In this study, we show differential contribution of monocytes to heart macrophages during steady state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure.
巨噬细胞存在于稳定状态的心肌中。此前，人们认为所有的巨噬细胞都来源于单核细胞；然而，有研究表明，在一些器官中，组织驻留巨噬细胞可能通过局部增殖来自我维持。
我们的目的是研究在 CD11b(DTR/+) 小鼠巨噬细胞耗竭后和心肌梗死后，单核细胞对稳定状态中心肌驻留巨噬细胞的贡献。
通过体内示踪和流式细胞术，我们估计在稳定状态下，心脏巨噬细胞群体大约每 1 个月更新一次。为了探索心脏驻留巨噬细胞的来源，我们通过联体共生使小鼠的循环系统相连。6 周后，我们观察到血液单核细胞嵌合率为 35.3±3.4%，而心脏巨噬细胞的嵌合率则低得多，为 2.7±0.5%（P<0.01）。巨噬细胞通过增殖实现局部自我更新：单次注射后 2 小时，有 2.1±0.3%的细胞摄取溴脱氧尿苷，有 13.7±1.4%的心脏巨噬细胞对细胞周期标志物 Ki-67 呈阳性反应。这些细胞可能参与了抗感染的防御，因为我们发现它们吞噬了荧光标记的细菌。在缺血性心肌中，我们观察到组织驻留巨噬细胞在局部死亡，而一些巨噬细胞也迁移到造血器官。如果稳定状态受到冠状动脉结扎或白喉毒素诱导的 CD11b(DTR/+) 小鼠巨噬细胞耗竭的干扰，血液单核细胞会补充心脏巨噬细胞。然而，在心肌梗死后的慢性阶段，驻留在梗死区的巨噬细胞再次独立于血液单核细胞池，恢复到稳定状态。
在这项研究中，我们展示了单核细胞在稳定状态下、巨噬细胞耗竭后或心肌梗死后的急性和慢性阶段对心脏巨噬细胞的不同贡献。我们发现巨噬细胞参与了心肌组织的免疫监视。这些数据与之前关于组织驻留巨噬细胞的研究结果一致，并提出了关于巨噬细胞在心力衰竭发展过程中的命运和功能的重要问题。
