Tissue Resident CCR2-and CCR2+Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury
Tissue Resident CCR2-and CCR2+Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury
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DOI：
10.1161/circresaha.118.314028
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发表时间：
2019-01-18
影响因子：
20.1
通讯作者：
Lavine, Kory J.
中科院分区：
文献类型：
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作者：
Bajpai, Geetika;Bredemeyer, Andrea;Lavine, Kory J.
理论基础：最近的研究进展揭示了组织巨噬细胞的起源、复杂性和功能。然而，在组织损伤或疾病的情况下，大量单核细胞浸润心脏，被认为有助于不良重塑和心力衰竭的发病机制。关于心肌损伤后募集到心脏的单核细胞和单核细胞衍生的巨噬细胞的多样性，包括调节单核细胞募集和命运规范的机制，人们知之甚少。目的：我们试图验证心肌损伤后组织内CCR2-（C-C趋化因子受体2）和CCR2+巨噬细胞的不同亚群协调单核细胞募集和命运规范的假设。方法和结果：我们发现，在许多心肌细胞死亡（永久性心肌梗死、再灌注心肌梗死和白喉毒素心肌细胞消融）的小鼠模型中，巨噬细胞的发生发生了转变，组织内的巨噬细胞主要被浸润性单核细胞和单核细胞来源的巨噬细胞所取代。利用同基因心脏移植模拟缺血再灌注损伤，并结合活体双光子显微镜区分组织常驻细胞群和募集细胞群，我们证明单核细胞募集是由不同亚群的组织常驻心脏巨噬细胞不同地协调的。组织驻留的CCR2+巨噬细胞通过MYD88（髓样分化初级反应88）依赖机制促进单核细胞募集，导致MCPs（单核细胞趋化蛋白）的释放和单核细胞动员。相反，组织内CCR2-巨噬细胞抑制单核细胞募集。通过对cd169 -DTR（白喉毒素受体）和CCR2- DTR小鼠的研究，我们进一步发现心肌梗死前组织内CCR2-或CCR2+巨噬细胞的选择性消耗对左心室功能、心肌重构和单核细胞募集的影响是不同的。最后，使用单细胞RNA测序，我们表明组织驻留的心脏巨噬细胞对单核细胞命运的指示存在差异。结论：总的来说，这些观察结果建立了单核细胞最初被招募到损伤心脏的机制基础，并为单核细胞来源的巨噬细胞的异质性提供了新的见解。
Rationale: Recent advancements have brought to light the origins, complexity, and functions of tissue-resident macrophages. However, in the context of tissue injury or disease, large numbers of monocytes infiltrate the heart and are thought to contribute to adverse remodeling and heart failure pathogenesis. Little is understood about the diversity of monocytes and monocyte-derived macrophages recruited to the heart after myocardial injury, including the mechanisms that regulate monocyte recruitment and fate specification.Objective: We sought to test the hypothesis that distinct subsets of tissue-resident CCR2-(C-C chemokine receptor 2) and CCR2+ macrophages orchestrate monocyte recruitment and fate specification after myocardial injury.Methods and Results: We reveal that in numerous mouse models of cardiomyocyte cell death (permanent myocardial infarction, reperfused myocardial infarction, and diphtheria toxin cardiomyocyte ablation), there is a shift in macrophage ontogeny whereby tissue-resident macrophages are predominately replaced by infiltrating monocytes and monocytederived macrophages. Using syngeneic cardiac transplantation to model ischemia-reperfusion injury and distinguish tissue-resident from recruited cell populations in combination with intravital 2-photon microscopy, we demonstrate that monocyte recruitment is differentially orchestrated by distinct subsets of tissue-resident cardiac macrophages. Tissue-resident CCR2+ macrophages promote monocyte recruitment through an MYD88 (myeloid differentiation primary response 88)-dependent mechanism that results in release of MCPs (monocyte chemoattractant proteins) and monocyte mobilization. In contrast, tissue-resident CCR2- macrophages inhibit monocyte recruitment. Using CD (cluster of differentiation) 169-DTR (diphtheria toxin receptor) and CCR2- DTR mice, we further show that selective depletion of either tissue-resident CCR2- or CCR2+ macrophages before myocardial infarction results in divergent effects on left ventricular function, myocardial remodeling, and monocyte recruitment. Finally, using single-cell RNA sequencing, we show that tissue-resident cardiac macrophages differentially instruct monocyte fate specification.Conclusions: Collectively, these observations establish the mechanistic basis by which monocytes are initially recruited to the injured heart and provide new insights into the heterogeneity of monocyte-derived macrophages.