From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women's Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart Center Freiburg, Freiburg, Germany (A.Z.); Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, CA (C.C.H.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Circ Res. 2014 May 9;114(10):1611-22. doi: 10.1161/CIRCRESAHA.114.303204. Epub 2014 Mar 13.
Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C)(high) and reparative Ly-6C(low) monocytes/macrophages (Mo/MΦ). According to 1 model, Mo/MΦ heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6C(low) monocyte production but dispensable to Ly-6C(low) macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity.
This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/MΦ accumulation scenarios.
We show that Ly-6C(high) monocytes infiltrate the infarcted myocardium and, unlike Ly-6C(low) monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6C(high) monocytes accrue in response to a brief C-C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6C(high) monocytes give rise to reparative Ly-6C(low) F4/80(high) macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C(high) monocytes express heightened levels of C-C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function.
Ly-6C(high) monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.
心肌梗死后的修复过程涉及炎症性淋巴细胞抗原 6C（Ly-6C）（高表达）和修复性 Ly-6C（低表达）单核细胞/巨噬细胞（Mo/MΦ）的双相积累。根据一种模型，心脏中 Mo/MΦ 的异质性起源于血液，并涉及到不同单核细胞亚群的顺序募集，这些亚群分化为不同的巨噬细胞。或者，异质性可能来源于 1 个循环亚群通过局部巨噬细胞分化和极化而在组织中产生。孤儿核受体，核受体亚家族 4，组 A，成员 1（Nr4a1）对 Ly-6C（低表达）单核细胞的产生是必需的，但对 Ly-6C（低表达）巨噬细胞的分化是可有可无的；因此，对 Nr4a1 的依赖性可以区分巨噬细胞异质性的系统性和局部起源。
本研究检测了 Nr4a1 在心肌梗死中的作用，并考虑了两种 Mo/MΦ 积累情况。
我们表明 Ly-6C（高表达）单核细胞浸润梗死的心肌，与 Ly-6C（低表达）单核细胞不同，它们分化为心脏巨噬细胞。在急性心肌缺血损伤的早期炎症阶段，Ly-6C（高表达）单核细胞因短暂的 C-C 趋化因子配体 2 爆发而积累。在第二个修复阶段，积累的 Ly-6C（高表达）单核细胞产生局部增殖的修复性 Ly-6C（低表达）F4/80（高表达）巨噬细胞。在 Nr4a1 缺失的情况下，Ly-6C（高表达）单核细胞表面表达更高水平的 C-C 趋化因子受体 2，强烈浸润心肌，并分化为异常炎症性巨噬细胞，导致愈合缺陷和心脏功能受损。
Ly-6C（高表达）单核细胞在心肌梗死后协调炎症和修复两个阶段，并依赖 Nr4a1 来限制其流入和炎症细胞因子的表达。
