A2bR-dependent signaling alters immune cell composition and enhances IL-6 formation in the ischemic heart
A2bR-dependent signaling alters immune cell composition and enhances IL-6 formation in the ischemic heart
复制标题
DOI：
10.1152/ajpheart.00029.2019
复制
发表时间：
2019-07-01
影响因子：
4.8
通讯作者：
Schrader, Jurgen
中科院分区：
文献类型：
--
作者：
Alter, Christina;Ding, Zhaoping;Schrader, Jurgen
尽管腺苷的心脏保护作用是无可争议的，但腺苷A(2b)受体(A(2b)R)在缺血性心脏重塑中的作用尚未明确。在本研究中，我们旨在揭示 A(2b)R 在调节免疫反应和心肌梗塞后愈合机制中的作用。 A(2b)R 的遗传和药理学 (PSB603) 灭活以及使用 BAY60-6583 激活 A(2b)R 不会改变梗死（50 分钟左前降支动脉闭塞/再灌注）小鼠心脏的心脏重塑。免疫细胞亚群的流式细胞术发现，A(2b)R 缺陷小鼠受伤心脏中的 B 细胞、NK 细胞、CD8 和 CD4 细胞以及表达 FoxP3 的调节性 T 细胞显着增加。 T 细胞功能分析表明，T 细胞的白细胞介素 (IL)-2、干扰素 (IFN)-γ 和肿瘤坏死因子 (TNF)α 的表达和分泌受 A(2b)R 控制。此外，我们发现免疫细胞和心肌细胞对A(2b)R缺陷的反应存在显着的细胞异质性：定量PCR测定，在缺乏A(2b)R的情况下，心肌细胞和除T细胞外的免疫细胞中IL-6的表达大大降低，心肌细胞、粒细胞和B细胞中IL-1β的表达显着降低。我们的研究结果表明，缺血心脏中的 A(2b)R 信号传导会引发心脏淋巴谱系免疫细胞组成的显着变化，并诱导 IL-6 和 IL-1 beta 的细胞类型特异性下调。这表明存在由缺血心脏形成的腺苷触发的可靶向腺苷-A(2b)R-IL-6轴。新的和值得注意的A(2b)R的基因缺失和药理学失活/激活不会改变MI后的心脏重塑，但与各种促炎和抗炎免疫细胞亚群（B细胞、NK细胞、CD8和CD4细胞、调节性T细胞）的代偿性上调相关。在发炎的心中。 A(2b)R 调节 T 细胞中 IL-2、IFN γ、TNF α 的表达以及心肌细胞、单核细胞、粒细胞和 B 细胞中 IL-6 的表达。这表明有一个重要的腺苷-IL-6 轴，该轴由 A(2b)R 通过局部腺苷控制。
Although the cardioprotective effect of adenosine is undisputed, the role of the adenosine A(2b) receptor (A(2b)R) in ischemic cardiac remodeling is not defined. In this study we aimed to unravel the role A(2b)R plays in modulating the immune response and the healing mechanisms after myocardial infarction. Genetic and pharmacological (PSB603) inactivation of A(2b)R as well as activation of A(2b)R with BAY60-6583 does not alter cardiac remodeling of the infarcted (50-min left anterior descending artery occlusion/reperfusion) murine heart. Flow cytometry of immune cell subsets identified a significant increase in B cells, NK cells, CD8 and CD4 cells, as well as FoxP3-expressing regulatory T cells in the injured heart in A(2b)R-deficient mice. Analysis of T-cell function revealed that expression and secretion of interleukin (IL)-2, interferon (IFN)-gamma, and tumor necrosis factor (TNF)alpha by T cells is under A(2b)R control. In addition, we found substantial cellular heterogeneity in the response of immune cells and cardiomyocytes to A(2b)R deficiency: while in the absence of A(2b)R, expression of IL-6 was greatly reduced in cardiomyocytes and immune cells except T cells, and expression of IL-1 beta was strongly reduced in cardiomyocytes, granulocytes, and B cells as determined by quantitative PCR. Our findings indicate that A(2b)R signaling in the ischemic heart triggers substantial changes in cardiac immune cell composition of the lymphoid lineage and induces a profound cell type-specific downregulation of IL-6 and IL-1 beta. This suggests the presence of a targetable adenosine-A(2b)R-IL-6-axis triggered by adenosine formed by the ischemic heart.NEW & NOTEWORTHY Genetic deletion and pharmacological inactivation/activation of A(2b)R does not alter cardiac remodeling after MI but is associated by compensatory upregulation of various pro-and anti-inflammatory immune cell subsets (B cells, NK cells. CD8 and CD4 cells, regulatory T cells). In the inflamed heart. A(2b)R modulates the expression of IL-2, IFN gamma, TNF alpha in T cells and of IL-6 in cardiomyocytes, monocytes, granulocytes and B cells. This suggests an important adenosine-IL-6 axis, which is controlled by A(2b)R via local adenosine.