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1 Department of Medicine, University of Virginia, Charlottesville, VA, USA
2 Department of Medicine, University of Virginia, Charlottesville, VA, USA; Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: mdo7y{at}virginia.edu.
The role of monocyte/macrophages in the pathogenesis of ischemia-reperfusion injury (IRI) is unknown. Furthermore we sought to determine whether activation of macrophage adenosine 2A receptors (A2ARs) mediates tissue protection. We performed IRI (32 min ischemia/24 hrs reperfusion) in C57Bl/6 mice infused with clodronate (dichloromethylene bisphosphonate; Cl2MBP) to deplete them of macrophages. IRI induced an elevation of plasma creatinine that was reduced with Cl2MBP (26% of control). Adoptive transfer of murine RAW 264.7 cells reconstituted injury, an effect blocked significantly by A2A-agonists (27% of
plasma creatinine from mice reconstituted with macrophages). Macrophages subjected to A2A-knock down by siRNA were adoptively transferred into
macrophage-deleted mice and reconstituted injury (110% of control mice), however the increase in plasma creatinine was blocked by A2A-agonists (20% of
vehicle treatment). Lastly, the A2A-agonist effect on IRI was blocked in macrophage-depleted A2AKO mice reconstituted with wild-type RAW 264.7 cells.
RNase protection assays at 24 hrs following IRI demonstrated that macrophages are required for IL-6 and TGF
mRNA induction. However A2A-agonist mediated tissue protection is independent of IL6 and TGF mRNA. We conclude that the full extent of IRI requires macrophages and that A2A-agonist-mediated tissue protection is independent of activation of macrophage A2ARs.
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