Anales RANF

P.91 IMPACT OF CD73-DERIVED ADENOSINE ON THE CELL-TYPE SPECIFIC CYTOKINE RESPONSE IN THE INFARCTED MURINE HEART C. Alter 1 , A.S. Henseler 1 , Z.Ding 1 , J.Scheller 1 , J.Schrader 1 1 Heinrich-Heine University Düsseldorf, North Rhine Westphalia, Germany In previous work we have shown that adenosine derived from CD73, expressed on T- cells, orchestrates the healing process after myocardial infarction, and that A2bR is specifically up-regulated on cardiomyocytes as well as on immune cell after infiltrating the infracted heart (Borg et al. (2017)). Here, we are exploring the cellular mechanisms by which CD73-derived adenosine is linked to cardiac cytokine response in the post infarct phase. CD4-CD73 -/- and A2bR -/- mice were subjected to 50 min occlusion of the left descending coronary artery with subsequent reperfusion. Three days post MI, coronary effluent perfusate was collected from isolated perfused hearts (Langendorff) and the cytokine profile (Bioplex) was determined. In CD4-CD73 -/- mice, cardiac IL-6 production was significantly reduced when compared to WT controls, suggesting that T-cell derived adenosine controls IL-6 in the heart. Since the A2bR was reported to also impact on IL-6 secretion e.g. in fibroblasts, we analyzed IL-6 expression (qPCR) in FACS-sorted cardiomyocytes, cardiac B-cells, T-cells, granulocytes and macrophages three days post MI in A2bR -/- mice. In all cell types analyzed – besides T-cells – IL-6 expression was significantly reduced compared to WT controls. Cardiac T-cells lacking A2bR showed an increase in pro-inflammatory cytokines (IL- 2, TNFα and IFNγ) in the post-MI heart. Finally, we stimulated human CD11b + CD14 + CD15 - monocytes with lipopolysaccharides in the presence or absence of the A2bR agonist BAY60-6583. Stimulation of A2bR strongly induced IL-6 secretion thereby emphasizing the importance of the adenosine - A2bR – IL-6 axis in the human system. Collectively our data indicate that CD73-derived adenosine acts via A2bR on the cytokine secretion of different cells types of the infarcted heart in a cell-type specific manner.