Lack of CXC Chemokine Receptor 3 Signaling Leads to Hypertrophic and Hypercellular Scarring

Abstract

CXC chemokine receptor 3 (CXCR3) signaling promotes keratinocyte migration while terminating fibroblast and endothelial cell immigration into wounds; this signaling also directs epidermal and matrix maturation. Herein, we investigated the long-term effects of failure to activate the "stop-healing" CXCR3 axis. Full-thickness excisional wounds were created on CXCR3 knockout((-/-)) or wild-type mice and examined at up to 180 days after wounding. Grossly, the CXCR3(-/-) mice presented a thick keratinized scar compared with the wild-type mice in which the scar was scarcely noticeable; histological examination revealed thickening of both the epidermis and dermis. The dermis was disorganized with thick and long collagen fibrils and contained excessive collagen content in comparison with the wild-type mice. Interestingly, the CXCR3(-/-) wounds presented lower tensile/burst strength, which correlates with decreased alignment of collagen fibers, similar to published findings of human scars. Persistent Extracellular matrix turnover and immaturity was shown by the elevated expression of proteins of the immature matrix as well as expression of matrix metallopeptidase-9 MMP-9. Interestingly, the scars in the CXCR3(-/-) mice presented evidence of de novo development of a sterile inflammatory response only months after wounding; earlier periods showed resolution of the initial inflammatory stage. These in vivo studies establish that the absence of CXCR3(-/-) signaling network results in hypertrophic and hypercellular scarring characterized by on-going wound regeneration, cellular proliferation, and scars in which immature matrix components are undergoing increased turnover resulting in a chronic inflammatory process.

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

“…95 In the absence of CXCR3, wounds remained immature with an inflammatory milieu and went on to develop a hypertrophic scar phenotype, similar to those observed in humans. 95 Taking this idea to its logical conclusion, the authors postulated that transplantation of normal fibroblasts to a CXCR3 -/-wound may lead to the correction of fibroblast-generated matrix dysfunction, resulting in improved healing. Not only did these normal fibroblasts survive within the wound milieu, they had a positive effect on healing, including matrix remodeling, improved collagen alignment, and increased tensile strength.…”

“…67,92,93 It is proposed that this signaling axis allows wounds to transition through remodeling resulting in the characteristic appearance of scar tissue with densely packed collagen bundles and reduced elastin. 94,95 Wound contraction secondary to myofibroblast action begins in the proliferative phase, but continues during remodeling.…”

“…95 To investigate the effect of a lack of CXCR3 receptors, wound healing and scarring was compared between CXCR3 -/ -and wild-type mice with full-thickness excisional wounds. 95 In the absence of CXCR3, wounds remained immature with an inflammatory milieu and went on to develop a hypertrophic scar phenotype, similar to those observed in humans.…”

“…95 To investigate the effect of a lack of CXCR3 receptors, wound healing and scarring was compared between CXCR3 -/ -and wild-type mice with full-thickness excisional wounds. 95 In the absence of CXCR3, wounds remained immature with an inflammatory milieu and went on to develop a hypertrophic scar phenotype, similar to those observed in humans. 95 Taking this idea to its logical conclusion, the authors postulated that transplantation of normal fibroblasts to a CXCR3 -/-wound may lead to the correction of fibroblast-generated matrix dysfunction, resulting in improved healing.…”

Integrin Regulation of Epidermal Functions in Wounds

“…Indeed, delays in wound re-epithelialization were associated with enhanced wound fibrosis, possibly due to a lack of signaling from epidermis, which may play a role in hypertrophic scar development. 135,149 Studies in co-culture models have demonstrated that many fibroblast genes are regulated by keratinocytederived factors, including genes coding for growth factors, ECM components, and MMPs, 136 all vital constituents for successful wound healing. Integrin a 3 b 1 is an intriguing candidate for influencing keratinocyte-to-fibroblast crosstalk in cutaneous wounds, given its above described role in promoting keratinocyte-to-endothelial cell crosstalk.…”