A_2bR-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_2bR) in ischemic cardiac remodeling is not defined. In this study we aimed to unravel the role A_2bR plays in modulating the immune response and the healing mechanisms after myocardial infarction. Genetic and pharmacological (PSB603) inactivation of A_2bR as well as activation of A_2bR 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 A_2bR-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 A_2bR control. In addition, we found substantial cellular heterogeneity in the response of immune cells and cardiomyocytes to A_2bR deficiency: while in the absence of A_2bR, 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 A_2bR 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-A_2bR-IL-6-axis triggered by adenosine formed by the ischemic heart. NEW & NOTEWORTHY Genetic deletion and pharmacological inactivation/activation of A_2bR 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, A_2bR 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 A_2bR via local adenosine.