Chemokine receptor CX3CR1 plays a central role in mediating skin wound healing

Wound healing is a complex process, involving the influx of neutrophils and macrophages initially, followed by angiogenesis and the transformation of fibroblasts into myofibroblasts that figure importantly in granulation tissue formation. As a result, a large number of chemokines are believed to participate in the healing process, including MCP-1/CCL2, MIP-1?/CCL3, and INF-?-inducible protein 10/CXCL10, plus the receptor CXCR2. The current paper builds upon this knowledge by demonstrating an important role for the chemokine CX3CL1 and its receptor CX3CR1.

Initially, gene expression for 9 chemokines and 6 inflammatory chemokine receptors was tracked following experimental skin wound. The results supported earlier findings that showed an increase in RNA of many chemokines during the first week after insult. Among these were RNA of CX3CL1 and its receptor CX3CR1, though the chemokine was induced prior to its receptor at the wound site. Elevation of CX3CL1 was normal in CX3CR1 knockout mice, but the time required to achieve a 40% wound closure was 40% longer (10 days, versus 6 days in wild-type mice). The delayed healing was characterized by 40% fewer macrophages at day 6 in the knockout mice, while the levels of neutrophils and CD3+ T cells were normal.

Further analyses revealed that CX3CR1 involvement in healing did not appear to be mediated through other cytokine-receptor complexes. Indeed, CX3CR1 was the dominant of the CX3CR1/CCR2 receptor phenotypes involved in macrophage recruitment. A study with the CX3CR1 knockout mice showed that it also participates in granulation tissue formation and collagen deposition in the wounded skin. The knockout animals exhibited lower TGF-?1, fibroblast accumulation, VEGF production, and new blood vessel formation than wild-type mice. These results were confirmed via the administration of antibodies against CX3CR1.

The present work identifies an important chemokine-receptor signaling pathway in the healing process through the attraction of macrophages and fibroblasts to the wound site and via either the direct or indirect stimulation of local angiogenesis. Thus, the CX3CR1 receptor affords a new target for creation of a localized wound-promoting therapy, suitable for hard-to-treat wounds. However, the results also raise a concern over the possible impact that systemic drugs, designed to inhibit inflammatory diseases (e.g., atherosclerosis, rheumatoid arthritis, and Crohn’s disease), might have on the normal healing process.

Message posted by: Keith Markey