ELR-negative CXC chemokine CXCL11 (IP-9/I-TAC) facilitates dermal and epidermal maturation during wound repair.
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.
Yates
Cecelia C
CC
Department of Pathology, University of Pittsburgh and Pittsburgh Veteran's Administration Medical Center, Pittsburgh, Pennsylvania 15261, USA.
Whaley
Diana
D
Y-Chen
Amy
A
Kulesekaran
Priya
P
Hebda
Patricia A
PA
Wells
Alan
A
D020816:Amino Acid Motifs; D000818:Animals; D054371:Chemokine CXCL11 / Q000378:metabolism*; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D054367:Receptors, CXCR3 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
D054371:Chemokine CXCL11; C515203:Cxcl11 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3