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Originally published online as doi:10.2353/ajpath.2007.061092 on June 28, 2007

Published online before print June 28, 2007
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(American Journal of Pathology. 2007;171:484-495.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061092

Delayed and Deficient Dermal Maturation in Mice Lacking the CXCR3 ELR-Negative CXC Chemokine Receptor

Cecelia C. Yates*, Diana Whaley*, Priya Kulasekeran*, Wayne W. Hancock{dagger}, Bao Lu{ddagger}, Richard Bodnar*, Joseph Newsome*, Patricia A. Hebda§ and Alan Wells*

From the Departments of Pathology,* and Otolaryngology,§ University of Pittsburgh and Pittsburgh VAMC, Pittsburgh, Pennsylvania; Millennium Pharmaceuticals, Incorporated,{dagger} Cambridge, Massachusetts; and Perlmutter Laboratory,{ddagger} Children’s Hospital, Boston, Massachusetts

Replacement of wounded skin requires the initially florid cellular response to abate and even regress as the dermal layer returns to a relatively paucicellular state. The signals that direct this "stop and return" process have yet to be deciphered. CXCR3 chemokine receptor and its ligand CXCL11/IP-9/I-TAC are expressed by basal keratinocytes and CXCL10/IP-10 by keratinocytes and endothelial cells during wound healing in mice and humans. In vitro, these ligands limit motility in dermal fibroblasts and endothelial cells. To examine whether this signaling pathway contributes to wound healing in vivo, full-thickness excisional wounds were created on CXCR3 wild-type (+/+) or knockout (–/–) mice. Even at 90 days, long after wound closure, wounds in the CXCR3–/– mice remained hypercellular and presented immature matrix components. The CXCR3–/– mice also presented poor remodeling and reorganization of collagen, which resulted in a weakened healed dermis. This in vivo model substantiates our in vitro findings that CXCR3 signaling is necessary for inhibition of fibroblast and endothelial cell migration and subsequent redifferentiation of the fibroblasts to a contractile state. These studies establish a pathophysiologic role for CXCR3 and its ligand during wound repair.






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Copyright © 2007 by the American Society for Investigative Pathology.