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.

中文翻译：

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心包脂肪组织调节心肌梗死后的粒细胞生成，纤维化和心脏功能。

背景技术心包脂肪组织（AT）包含高密度的淋巴样簇。尚不清楚这些簇是否在心肌梗死后（MI）炎症反应和心脏预后中起作用。方法在有或没有冠心病的人的心外膜AT中检查淋巴簇。在进行冠状动脉结扎的小鼠中观察到小鼠心包淋巴样簇。为了研究心梗后炎症反应期间心包簇的相关性，我们手术切除了心包膜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。通过流式细胞术对小鼠心脏，心包膜AT，脾脏，纵隔淋巴结和骨髓中的白细胞进行定量。大麻素受体CB2（CB2-/-）小鼠被用作增强B细胞反应的模型。在遭受MI的CCR7-/-小鼠中测试了受损的树突状细胞（DC）交易对心包AT炎性反应的影响。通过组织学和超声心动图评估心脏纤维化和心室功能。结果与没有冠心病的对照组相比，我们在患有冠心病的人类患者的心外膜AT中发现了较大的B细胞簇。梗塞的小鼠还具有较大的心包簇，在心包AT内的粒细胞-巨噬细胞集落刺激因子产生B细胞上调了3倍，但没有脾脏或淋巴结肿大。这与心包AT中较高的DC和T细胞计数有关，后者超过淋巴结中的DC和T细胞。直流成熟标记的分析，荧光标记细胞的追踪实验以及使用CCR7缺陷型小鼠的研究表明，活化的DC通过CCR7从梗塞迁移至心包膜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DC和T细胞的扩增，并在MI后3天转化为骨髓粒细胞减少和心脏中性粒细胞浸润。通过去除心包膜AT以及与心包膜AT和粒细胞祖细胞离体共培养，证实了心包膜AT在介导所有这些作用中的相关性。最后，CB2-/-小鼠的纤维化增强和射血分数恶化受到心包AT去除的限制。结论我们的发现揭示了一种新的机制，通过该机制心包膜AT可以协调免疫细胞激活，粒细胞生成，