ELR-negative CXC chemokine CXCL11 (IP-9/I-TAC) facilitates dermal and epidermal maturation during wound repair

Am J Pathol. 2008 Sep;173(3):643-52. doi: 10.2353/ajpath.2008.070990. Epub 2008 Jul 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Chemokine CXCL11 / metabolism*
  • Dermis / metabolism*
  • Dermis / pathology
  • Epidermis / metabolism*
  • Epidermis / pathology
  • Female
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Male
  • Mice
  • Mice, Transgenic
  • Receptors, CXCR3 / metabolism
  • Signal Transduction / physiology*
  • Wound Healing / physiology*

Substances

  • Chemokine CXCL11
  • Cxcl11 protein, mouse
  • Cxcr3 protein, mouse
  • Receptors, CXCR3