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Originally published online as doi:10.2353/ajpath.2008.070990 on July 31, 2008

Published online before print July 31, 2008
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(American Journal of Pathology. 2008;173:643-652.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070990

ELR-Negative CXC Chemokine CXCL11 (IP-9/I-TAC) Facilitates Dermal and Epidermal Maturation during Wound Repair

Cecelia C. Yates*{dagger}, Diana Whaley*, Amy Y-Chen*, Priya Kulesekaran*, Patricia A. Hebda{ddagger} and Alan Wells*{dagger}

From the Departments of Pathology* and Otolaryngology,{ddagger} University of Pittsburgh and Pittsburgh Veteran’s Administration Medical Center, Pittsburgh, Pennsylvania; and the Carver Research Foundation,{dagger} Tuskegee University, Tuskegee, Alabama

In skin wounds, the chemokine CXCR3 receptor appears to play a key role in coordinating the switch from regeneration of the ontogenically distinct mesenchymal and epithelial compartments toward maturation. However, because CXCR3 equivalently binds four different ELR-devoid CXC chemokines (ie, PF4/CXCL4, IP-10/CXCL10, MIG/CXCL9, and IP-9/CXCL11), we sought to identify the ligand that coordinates epidermal coverage with the maturation of the underlying superficial dermis. Because CXCL11 (IP-9 or I-TAC) is produced by redifferentiating keratinocytes late in the regenerative phase when re-epithelialization is completed and matrix maturation ensues, we generated mice in which an antisense construct (IP-9AS) eliminated IP-9 expression during the wound-healing process. Both full and partial thickness excisional wounds were created and analyzed histologically throughout a 2-month period. Wound healing was impaired in the IP-9AS mice, with a hypercellular and immature dermis noted even after 60 days. Re-epithelialization was delayed with a deficient delineating basement membrane persisting in mice expressing the IP-9AS construct. Provisional matrix components persisted in the dermis, and the mature basement membrane components laminin V and collagen IV were severely diminished. Interestingly, the inflammatory response was not diminished despite IP-9/I-TAC being chemotactic for such cells. We conclude that IP-9 is a key ligand in the CXCR3 signaling system for wound repair, promoting re-epithelialization and modulating the maturation of the superficial dermis.






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Copyright © 2008 by the American Society for Investigative Pathology.