Inactivation of the adenosine A2A receptor (A2AR) consistently protects against ischemic brain injury and other neural insults, but the relative contribution of A2ARs on peripheral inflammatory cells versus A2ARs expressed on neurons and glia is unknown. We created a chimeric mouse model in which A2ARs on bone marrow–derived cells (BMDCs) were selectively inactivated or reconstituted by bone marrow transplantation. Selective reconstitution of A2ARs on BMDCs (A2AR knockout mice transplanted with wild-type bone marrow cells) largely reinstates ischemic brain injury in global A2AR knockout mice. Conversely, selective inactivation of A2ARs on BMDCs (wild-type mice transplanted with A2AR knockout bone marrow cells) attenuates infarct volumes and ischemia-induced expression of several proinflammatory cytokines in the brain, but exacerbates ischemic liver injury. These results indicate that the A2AR-stimulated cascade in BMDCs is an important modulator of ischemic brain injury and that ischemic brain and liver injuries are regulated distinctly by A2ARs on BMDCs.
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We thank B.B. Fredholm and M.A. Schwarzschild for discussion and critical reading of the manuscript and D. Xu for assistance with FACS analysis. This work was supported in part by grants NS37403, NS41083 (J-F.C.) and NS-10828 (M.M.) from the US National Institutes of Health and by Bumpus Foundation (J-F.C.).
The authors declare no competing financial interests.
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