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Fractalkine induces angiogenic potential in CX3CR1‐expressing monocytes

We report the unique role of CX3CL1 (or fractalkine) on CD11b+ myelomonocytic cells expressing CX3CR1, the only known receptor for CX3CL1, in promoting blood perfusion recovery. In a mouse ischemic hind‐limb model, CD11b+CX3CR1+ cells migrated to ischemic femoral muscles through CX3CL1‐mediated chemotaxis. CD11b+CX3CR1+ macrophages isolated from ischemic tissues [tissue (T)‐CD11b+CX3CR1+] of muscle exert a proangiogenic effect through platelet factor‐4 (CXCL4; PF‐4) production. PF‐4 does not promote angiogenesis by itself but, instead, increases VEGF‐mediated angiogenesis. Despite proangiogenic effects of muscle‐derived T‐CD11b+CX3CR1+ macrophages, their clinical implementation is limited because muscle excision is required for cell harvesting. Therefore, we focused on the more accessible bone marrow (BM)‐CD11b+CX3CR1+ monocytes, which migrate from BM into ischemic muscles via CX3CL1‐mediated chemotaxis. PF‐4 expression was not detected in BM‐CD11b+CX3CR1+ monocytes under normal conditions, but CX3CL1 (50 ng/ml) induced high PF‐4 expression and enabled BM‐CD11b+CX3CR1+ monocytes to achieve a similar angiogenic potential to that of T‐CD11b+CX3CR1+ macrophages ex vivo. Furthermore, we were able to identify a subset of monocytes that express CD11b and CX3CR1 in human peripheral blood and confirmed the proangiogenic effect of CX3CL1 treatment. Thus, CX3CL1‐treated CD11b+CX3CR1+ monocytes may be of potential therapeutic use to significantly accelerate recovery of blood perfusion in ischemic diseases.