Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration
Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration
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Dectin-1 通过调节巨噬细胞极化和中性粒细胞浸润导致心肌缺血/再灌注损伤
DOI：
10.1161/circulationaha.118.036044
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发表时间：
2019-01-29
期刊：
影响因子：
37.8
通讯作者：
Yan, Xiaoxiang
中科院分区：
文献类型：
--
作者：
Fan, Qin;Tao, Rong;Yan, Xiaoxiang
背景：巨噬细胞相关免疫反应在心肌缺血/再灌注损伤中起重要作用。Dectin-1主要表达于活化的骨髓细胞上，作为模式识别受体对于调节免疫稳态至关重要。但其在心肌缺血再灌注损伤中的作用及机制尚不清楚。研究方法：基因消除、抗体阻断或Dectin-1活化，沿着过继骨髓转移嵌合模型，用于确定Dectin-1在心肌IR损伤中的功能意义。通过流式细胞术、实时定量聚合酶链反应和免疫组织化学检测免疫细胞过滤和炎症。此外，通过流式细胞术分析ST段抬高型心肌梗死患者和冠状动脉正常的稳定患者（对照）血液中的Dectin-1+细胞。结果如下：我们证明，在IR损伤后的早期阶段，心脏中骨髓源性巨噬细胞上观察到的Dectin-1表达增加。Dectin-1缺陷和抗体介导的Dectin-1抑制导致心脏功能的显著改善，伴随着心肌细胞凋亡的减少，这与M1巨噬细胞极化和Ly-6C+单核细胞和中性粒细胞浸润的减少有关。用其激动剂激活Dectin-1具有相反的效果。此外，Dectin-1有助于通过调节Cxcl 1和粒细胞集落刺激因子的表达，中性粒细胞的招聘。此外，Dectin-1依赖性白细胞介素-23/白细胞介素-1的产生被证明是T细胞表达白细胞介素-17A所必需的，导致中性粒细胞募集和心肌IR损伤。此外，我们证明了ST段抬高型心肌梗死患者的循环Dectin-1+ CD 14 ++ CD 16 −和Dectin-1+ CD 14 ++ CD 16+单核细胞水平显著高于对照组，并与心功能不全的严重程度呈正相关。结论：我们的研究结果揭示了Dectin-1在小鼠心肌IR损伤过程中的关键作用，并提供了一个新的，具有临床意义的治疗靶点。
Background: Macrophage-associated immune response plays an important role in myocardial ischemia/reperfusion (IR) injury. Dectin-1, expressed mainly on activated myeloid cells, is crucial for the regulation of immune homeostasis as a pattern recognition receptor. However, its effects and roles during the myocardial IR injury remain unknown. Methods: Genetic ablation, antibody blockade, or Dectin-1 activation, along with the adoptive bone marrow transfer chimeric model, was used to determine the functional significance of Dectin-1 in myocardial IR injury. Immune cell filtration and inflammation were examined by flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Moreover, Dectin-1+ cells were analyzed by flow cytometry in the blood of patients with ST-segment–elevation myocardial infarction and stable patients with normal coronary artery (control). Results: We demonstrated that Dectin-1 expression observed on the bone marrow–derived macrophages is increased in the heart during the early phase after IR injury. Dectin-1 deficiency and antibody-mediated Dectin-1 inhibition led to a considerable improvement in cardiac function, accompanied by a reduction in cardiomyocyte apoptosis, which was associated with a decrease in M1 macrophage polarization and Ly-6C+ monocyte and neutrophil infiltration. Activation of Dectin-1 with its agonist had the opposite effects. Furthermore, Dectin-1 contributed to neutrophil recruitment through the regulation of Cxcl1 and granulocyte colony-stimulating factor expression. In addition, Dectin-1–dependent interleukin-23/interleukin-1&bgr; production was shown to be essential for interleukin-17A expression by &ggr;&dgr;T cells, leading to neutrophil recruitment and myocardial IR injury. Furthermore, we demonstrated that circulating Dectin-1+CD14++CD16− and Dectin-1+CD14++CD16+ monocyte levels were significantly higher in patients with ST-segment–elevation myocardial infarction than in controls and positively correlated with the severity of cardiac dysfunction. Conclusions: Our results reveal a crucial role of Dectin-1 in the process of mouse myocardial IR injury and provide a new, clinically significant therapeutic target.