American Society for Investigative Pathology, June 2010, Vol 2, No. 2

Hot off the Press

Lack of CXC Chemokine Receptor 3 Signaling Leads to Hypertrophic and Hypercellular Scarring
Yates CC, Krishna F, Whaley D, Bodnar R, Turner T, Wells A.
From the Department of Pathology, University of Pittsburgh, Pittsburgh Veteran Affairs Medical Center, Pittsburgh, Pennsylvania; and Tuskegee University Center for Cancer Research, Tuskegee, Alabama
Am. J. Pathol. 2010 176: 1743-1755

A synopsis written by co-author and ASIP trainee Dr. Cecelia C. Yates at the University of Pittsburgh School of Medicine Department of Pathology

The wound repair process occurs in tissues after exposure to almost any destructive stimulus. To restore tissue integrity and homeostatic functioning, many cellular pathways must be activated and coordinated immediately after injury occurs. However, disrupting this regenerative replacement is the development of scarring. Scar formation is a consequence of a dysfunction in remodeling two skin compartments; the ectodermally–derived epithelial epidermis and the mesodermally–derived mesenchymal dermis. Hypertrophic scar formation, resulting in a thickened skin, which is raised above the unwounded tissue, is caused by increased wound cellularity and excessive matrix. Hypertrophic scar formation is a major clinical problem followingburn injuries, traumatic injuries, and surgical procedures, and leads to permanent functional loss as well as psychological problems for patients.

Regeneration and scarring are controlled by soluble peptide factors, signaling, cellproliferation and migration into the wound. Various differentiation functions are inducedincluding wound contraction, epidermal stratification, and dermal remodeling. Prominent during all stages of wound repair are growth factor receptors and ligands that induce fibroblast and keratinocyte motility and proliferation. However, the equally important ‘stop’ and differentiation signals have not been fully elucidated. A series of observations by A.Wells and colleagues has noted that exuberant cellular responses of wound repair are resolved towards to end of the healing process, at least in part, by chemokines that appear in the late remodeling and resolving phase of repair. In particular, chemokines binding to the ubiquitous seven transmembrane G-protein couple chemokine receptor, CXCR3, CXCL10 and CXCL11. The effect of global CXCR3 deletion results in wounds that mature at a retarded rate with an immature and weakened dermis. In fact, loss of the CXCR3 signaling system has revealed that over extended periods of time the protracted and incomplete healing was followed by a reemergence of inflammation and excessive scarring months after skin injury.

A recent report (Yates et al, Am J Pathol2010 Apr;176(4); 1588-91) establishes that in the absence of CXCR3signaling hypertrophic and hypercellular scarring develops months after the initial wound insult. This scarring is characterized by on-going wound regeneration, cellular proliferation, and increasing turnover of immature matrix components resulting in a chronic inflammatory process. In vivo wounding studies in CXCR3-/- mice demonstrated that dermal wounds that were disorganized with thick and long collagen fibrils, excessive collagen content, and interestingly lower tensile/burst strength which correlates with decreased alignment of collagen fibers. This is similar tohypertrophic scars in humans.The immaturity of the matrix constituency has implications beyond diminished strength. Fibronectin and tenascin C exhibits an altering adhesiveprofile, with implications that the feed-forward loop in which these matrix proteins normally promote healing not only fails to complete the healing cascade but remains in an active immature state contributing to the further cell-driven scarring in the absence of CXCR3.

These findings go beyond the earlier studies demonstrating a central role for CXCR3 signaling in wound resolution but show that the cessation of the regenerative phase of healing is necessary to prevent longer term stromal cell-driven chronic inflammation. This highlights the matrix composition as not just the result of inflammation but actively contributes to the inflammatory and fibrotic process. In addition, the absence of CXCR3 defines a novel animal model for persistent healing and hypertrophic scarring. In many ways, the properties of these wounds are reminiscent of human hypertrophic scars and keloid dysplasia. Therefore modulation of the CXCR3 signaling axis could show great promise as a therapeutic tool for turning on and off wound scarring.