Systemic and Cardiac Depletion of M2 Macrophage through CSF-1R Signaling Inhibition Alters Cardiac Function Post Myocardial Infarction.
Systemic and Cardiac Depletion of M2 Macrophage through CSF-1R Signaling Inhibition Alters Cardiac Function Post Myocardial Infarction.
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DOI：
10.1371/journal.pone.0137515
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Caplice NM
中科院分区：
文献类型：
--
作者：
Leblond AL;Klinkert K;Martin K;Turner EC;Kumar AH;Browne T;Caplice NM
心脏宿主组织驻留的巨噬细胞能够通过多种机制调节心脏炎症和功能。目前，心脏巨噬细胞表型多样性的后果还不完全清楚。心肌M2极化巨噬细胞对心肌梗死后炎症反应和修复反应的作用仍有待充分研究。在本研究中，利用特异性CSF-1受体信号传导抑制策略研究了M2巨噬细胞的作用，以实现其耗竭。在小鼠中，口服GW 2580（一种CSF-1 R激酶抑制剂）可诱导循环和脾脏中Gr 1 lo和F4/80 hi单核细胞群显著减少。GW 2580给药1周后还诱导了心脏中M2巨噬细胞的显著消耗，以及心脏巨噬细胞酶1和CD 206基因表达的减少，表明M2巨噬细胞活性。在鼠心肌梗死模型中，与溶媒给药对照组相比，GW 2580给药组动物心脏中M2巨噬细胞含量降低与M1相关基因表达（IL-6和IL-1β）增加和M2相关基因表达（精氨酸酶1和CD 206）降低相关。M2耗竭还与左心室收缩功能丧失、梗死扩大、胶原染色减少和梗死区炎性细胞浸润增加相关，特别是中性粒细胞和M1巨噬细胞。总之，这些数据表明，CSF-1 R信号传导对于维持心脏组织驻留的M2极化巨噬细胞群是至关重要的，这是心肌梗死后炎症消退所需的，进而是心室功能的保护。
The heart hosts tissue resident macrophages which are capable of modulating cardiac inflammation and function by multiple mechanisms. At present, the consequences of phenotypic diversity in macrophages in the heart are incompletely understood. The contribution of cardiac M2-polarized macrophages to the resolution of inflammation and repair response following myocardial infarction remains to be fully defined. In this study, the role of M2 macrophages was investigated utilising a specific CSF-1 receptor signalling inhibition strategy to achieve their depletion. In mice, oral administration of GW2580, a CSF-1R kinase inhibitor, induced significant decreases in Gr1lo and F4/80hi monocyte populations in the circulation and the spleen. GW2580 administration also induced a significant depletion of M2 macrophages in the heart after 1 week treatment as well as a reduction of cardiac arginase1 and CD206 gene expression indicative of M2 macrophage activity. In a murine myocardial infarction model, reduced M2 macrophage content was associated with increased M1-related gene expression (IL-6 and IL-1β), and decreased M2-related gene expression (Arginase1 and CD206) in the heart of GW2580-treated animals versus vehicle-treated controls. M2 depletion was also associated with a loss in left ventricular contractile function, infarct enlargement, decreased collagen staining and increased inflammatory cell infiltration into the infarct zone, specifically neutrophils and M1 macrophages. Taken together, these data indicate that CSF-1R signalling is critical for maintaining cardiac tissue resident M2-polarized macrophage population, which is required for the resolution of inflammation post myocardial infarction and, in turn, for preservation of ventricular function.