Wound healing is a complex physiologic process that proceeds in overlapping, sequential steps.
Plasminogen promotes fibrinolysis and potentiates the inflammatory response during wound healing. We have tested the hypothesis that the novel
plasminogen receptor, Plg-RKT, regulates key steps in wound healing. Standardized
burn wounds were induced in mice and time dependence of
wound closure was quantified. Healing in Plg-RKT-/- mice was significantly delayed during the proliferation phase. Expression of inflammatory
cytokines was dysregulated in Plg-RKT-/-
wound tissue. Consistent with dysregulated
cytokine expression, a significant delay in wound healing during the proliferation phase was observed in mice in which Plg-RKT was specifically deleted in myeloid cells. Following
wound closure, the epidermal thickness was less in Plg-RKT-/-
wound tissue. Paradoxically, deletion of Plg-RKT, specifically in keratinocytes, significantly accelerated the rate of healing during the proliferation phase. Mechanistically, only two genes were upregulated in Plg-RKT-/- compared with Plg-RKT+/+
wound tissue,
filaggrin, and
caspase 14. Both
filaggrin and
caspase 14 promote epidermal differentiation and decrease proliferation, consistent with more rapid
wound closure and decreased epidermal thickness during the remodeling phase.
Fibrin clearance was significantly impaired in Plg-RKT-/-
wound tissue. Genetic reduction of
fibrinogen levels to 50% completely abrogated the effect of Plg-RKT deletion on the healing of
burn wounds. Remarkably, the effects of Plg-RKT deletion on
cytokine expression were modulated by reducing
fibrinogen levels. In summary, Plg-RKT is a new regulator participating in different phases of cutaneous
burn wound healing, which coordinately plays a role in the interrelated responses of
inflammation, keratinocyte migration, and fibrinolysis.