A2bR-dependent signaling alters immune cell composition and enhances IL-6 formation in the ischemic heart

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.