Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 103, Issue 1, Pages 53-66Publisher
WILEY
DOI: 10.1189/jlb.1A0117-002RR
Keywords
angiogenesis; CX3CR1; CX3CL1; monocyte
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Funding
- Catholic Medical Center Research Foundation
- St. Vincent's Hospital, Research Institute of Medical Science
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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.
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