Dectin-2 Deficiency Modulates Th1 Differentiation and Improves Wound Healing After Myocardial Infarction
Dectin-2 Deficiency Modulates Th1 Differentiation and Improves Wound Healing After Myocardial Infarction
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Dectin-2 缺乏调节 Th1 分化并改善心肌梗塞后伤口愈合
DOI：
10.1161/circresaha.116.310260
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发表时间：
2017-03-31
影响因子：
20.1
通讯作者：
Zhang, Ruiyan
中科院分区：
文献类型：
--
作者：
Yan, Xiaoxiang;Zhang, Hang;Zhang, Ruiyan
原理：大环内酯参与心肌梗死（MI）后的伤口愈合。Dectin-2是一种主要表达于骨髓细胞的模式识别受体，其在心肌梗死愈合中的作用尚不清楚。目的：本研究的目的是确定Dectin-2信号通路是否参与心肌梗死后的愈合过程和心脏重塑，并阐明其潜在的分子机制。在永久性冠状动脉结扎的小鼠模型中，显示主要在巨噬细胞中表达的Dectin-2在MI后的早期阶段增加。与野生型小鼠相比，Dectin-2基因敲除小鼠在梗死愈合和心脏重塑方面表现出改善，这通过心脏破裂导致的死亡率显著降低、壁厚增加和心脏功能改善来证明。心肌梗死后，Dectin-2基因敲除小鼠心脏中α-平滑肌肌动蛋白和胶原蛋白I/III的表达增加，而基质金属蛋白酶-2和基质金属蛋白酶-9的水平降低。Dectin-2缺陷抑制凋亡和坏死细胞死亡的速率。然而，Dectin-2并不影响免疫细胞浸润和巨噬细胞极化，但它通过增强心脏中白细胞介素-12的产生而导致Th 1/干扰素-γ免疫反应的更强激活。干扰素-γ显示下调转化生长因子-α诱导的分离的心脏成纤维细胞中α-平滑肌肌动蛋白和胶原蛋白I/III的表达，导致迁移和肌成纤维细胞分化减少。最后，Dectin-2敲除改善心肌缺血-再灌注损伤和梗死health.Conclusions：Dectin-2导致心脏破裂的增加，损害伤口愈合，并通过调节Th 1分化，减轻心肌梗死后的心脏重塑。
Rationale: Macrophages are involved in wound healing after myocardial infarction (MI). The role of Dectin-2, a pattern recognition receptor mainly expressed on myeloid cells, in the infarct healing remains unknown.Objective: The aim of this study is to determine whether Dectin-2 signaling is involved in the healing process and cardiac remodeling after MI and to elucidate the underlying molecular mechanisms.Methods and Results: In a mouse model of permanent coronary ligation, Dectin-2, mainly expressed in macrophages, was shown to be increased in the early phase after MI. Dectin-2 knockout mice showed an improvement in the infarct healing and cardiac remodeling, compared with wild-type mice, which was demonstrated by significantly lower mortality because of cardiac rupture, increased wall thickness, and better cardiac function. Increased expression of a-smooth muscle actin and collagen I/III was observed, whereas the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 were decreased in the hearts of Dectin-2 knockout mice after MI. Dectin-2 deficiency inhibited the rate of apoptotic and necrotic cell death. However, Dectin-2 did not affect immune cell infiltration and macrophage polarization, but it led to a stronger activation of the Th1/interferon-gamma immune reaction, through the enhancement of interleukin-12 production in the heart. Interferon-gamma was shown to downregulate transforming growth factor-alpha-induced expression of a-smooth muscle actin and collagen I/III in isolated cardiac fibroblasts, leading to a decrease in migration and myofibroblast differentiation. Finally, Dectin-2 knockout improved myocardial ischemia-reperfusion injury and infarct healing.Conclusions: Dectin-2 leads to an increase in cardiac rupture, impairs wound healing, and aggravates cardiac remodeling after MI through the modulation of Th1 differentiation.