Pericardial Adipose Tissue Regulates Granulopoiesis, Fibrosis, and Cardiac Function After Myocardial Infarction
Pericardial Adipose Tissue Regulates Granulopoiesis, Fibrosis, and Cardiac Function After Myocardial Infarction
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DOI：
10.1161/circulationaha.117.028833
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发表时间：
2018-02-27
期刊：
影响因子：
37.8
通讯作者：
Steffens, Sabine
中科院分区：
文献类型：
--
作者：
Horckmans, Michael;Bianchini, Mariaelvy;Steffens, Sabine
背景：心包脂肪组织（AT）含有高密度的淋巴簇。目前尚不清楚这些集群是否发挥作用，在心肌梗死后（MI）炎症反应和心脏outcome.METHODS：类棘球蛋白集群进行了检查，在心外膜AT的人或没有冠状动脉疾病。在冠状动脉结扎的小鼠中观察到鼠心包淋巴簇。为了研究心肌梗死后炎症反应期间心包簇的相关性，我们手术切除了心包AT，并进行了B细胞耗竭和粒细胞-巨噬细胞集落刺激因子阻断。通过流式细胞术定量小鼠心脏、心包AT、脾脏、纵隔淋巴结和骨髓中的白细胞。大麻素受体CB 2（CB 2（-/-））小鼠用作增强的B细胞应答的模型。在经历MI的CCR 7（-/-）小鼠中测试受损的树突状细胞（DC）运输对心包AT炎症反应的影响。心脏纤维化和心室功能进行了评估，组织学和超声心动图。结果：我们确定了较大的B细胞簇在心外膜AT的人类患者与冠状动脉疾病相比，对照组无冠状动脉疾病。切除的小鼠还具有更大的心包簇和心包AT内产生粒细胞-巨噬细胞集落刺激因子的B细胞数量上调3倍，但脾脏或淋巴结没有。这与心包AT中较高的DC和T细胞计数相关，其数量超过淋巴结中的DC和T细胞。DC成熟标记物的分析、荧光标记细胞的跟踪实验以及CCR 7缺陷小鼠的使用表明，活化的DC通过CCR 7从梗死迁移到心包AT。B细胞耗竭或粒细胞-巨噬细胞集落刺激因子中和抑制了心包AT内的DC和T细胞扩增，并在MI后3天转化为骨髓粒细胞生成减少和心脏中性粒细胞浸润。心包AT在介导所有这些效应中的相关性通过去除心包AT以及与心包AT和粒细胞祖细胞的离体共培养来证实。最后，增强的纤维化和恶化的射血分数在CB 2（-/-）小鼠被限制心包AT removal.CONCLUSIONS：我们的研究结果揭示了一个新的机制，心包AT协调免疫细胞激活，粒细胞生成，MI后的结果。
BACKGROUND: The pericardial adipose tissue (AT) contains a high density of lymphoid clusters. It is unknown whether these clusters play a role in post-myocardial infarction (MI) inflammatory responses and cardiac outcome.METHODS: Lymphoid clusters were examined in epicardial AT of humans with or without coronary artery disease. Murine pericardial lymphoid clusters were visualized in mice subjected to coronary artery ligation. To study the relevance of pericardial clusters during inflammatory responses after MI, we surgically removed the pericardial AT and performed B-cell depletion and granulocyte-macrophage colony-stimulating factor blockade. Leukocytes in murine hearts, pericardial AT, spleen, mediastinal lymph nodes, and bone marrow were quantified by flow cytometry. Cannabinoid receptor CB2 (CB2(-/-)) mice were used as a model for enhanced B-cell responses. The effect of impaired dendritic cell (DC) trafficking on pericardial AT inflammatory responses was tested in CCR7(-/-) mice subjected to MI. Cardiac fibrosis and ventricular function were assessed by histology and echocardiography.RESULTS: We identified larger B-cell clusters in epicardial AT of human patients with coronary artery disease in comparison with controls without coronary artery disease. Infarcted mice also had larger pericardial clusters and 3-fold upregulated numbers of granulocyte-macrophage colony-stimulating factor-producing B cells within pericardial AT, but not spleen or lymph nodes. This was associated with higher DC and T-cell counts in pericardial AT, which outnumbered DCs and T cells in lymph nodes. Analysis of DC maturation markers, tracking experiments with fluorescently labeled cells, and use of CCR7-deficient mice suggested that activated DCs migrate from infarcts into pericardial AT via CCR7. B-cell depletion or granulocyte-macrophage colony-stimulating factor neutralization inhibited DC and T-cell expansion within pericardial AT, and translated into reduced bone marrow granulopoiesis and cardiac neutrophil infiltration 3 days after MI. The relevance of the pericardial AT in mediating all these effects was confirmed by removal of pericardial AT and ex vivo coculture with pericardial AT and granulocyte progenitors. Finally, enhanced fibrosis and worsened ejection fraction in CB2(-/-) mice were limited by pericardial AT removal.CONCLUSIONS: Our findings unveil a new mechanism by which the pericardial AT coordinates immune cell activation, granulopoiesis, and outcome after MI.