Synergy between Toll-like receptor (TLR) and adenosine A 2A receptor (A 2A R) signaling switches macrophages from production of inflammatory cytokines such as tumor necrosis factor-␣ to production of the angiogenic growth factor vascular endothelial growth factor (VEGF). We show in this study that this switch critically requires signaling through MyD88, IRAK4, and TRAF6. Macrophages from mice lacking MyD88 (MyD88 ؉/؉ wounds and stimulated angiogenesis but had no significant effect on healing of MyD88 ؊/؊ wounds. These results suggest that the synergistic interaction between TLR and A 2A R signaling observed in vitro that switches macrophages from an inflammatory to an angiogenic phenotype also plays a role in wound healing in vivo.