AR-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 receptor (AR) in ischemic cardiac remodeling is not defined. In this study we aimed to unravel the role AR plays in modulating the immune response and the healing mechanisms after myocardial infarction. Genetic and pharmacological (PSB603) inactivation of AR as well as activation of AR 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 T cells, as well as FoxP3-expressing regulatory T cells in the injured heart in AR-deficient mice. Analysis of T-cell function revealed that expression and secretion of interleukin (IL)-2, interferon (IFN)γ, and tumor necrosis factor (TNF)α by T cells is under AR control. In addition, we found substantial cellular heterogeneity in the response of immune cells and cardiomyocytes to AR deficiency: while in the absence of AR, expression of IL-6 was greatly reduced in cardiomyocytes and immune cells except T cells, and expression of IL-1β was strongly reduced in cardiomyocytes, granulocytes, and B cells as determined by quantitative PCR. Our findings indicate that AR 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-1β. This suggests the presence of a targetable adenosine-AR-IL-6-axis triggered by adenosine formed by the ischemic heart. Genetic deletion and pharmacological inactivation/activation of AR 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 T cells, regulatory T cells). In the inflamed heart, AR modulates the expression of IL-2, IFNγ, TNFα 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 AR via local adenosine.