The plasminogen receptor, Plg-RKT, plays a role in inflammation and fibrinolysis during cutaneous wound healing in mice

Lina Ny,Malgorzata Wilczynska,Assar Bäckman,Robert J Parmer,Sandra Holmberg,Nagyung Baik,Lindsey A Miles,Yue Shen,Jessica Broden,Tor Ny

doi:10.1038/s41419-020-03230-1

Abstract

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.

Highlights

Wound healing is a fundamental and complex physiologic process that proceeds in overlapping, sequential steps[1]
Plasmin directly promotes keratinocyte migration[16] and the role of plasmin was considered to be the promotion of keratinocyte migration by allowing keratinocytes to dissect their way through the fibrin-rich extracellular matrix (ECM) by cleaving components of the ECM12,17
Reepithelialization eventually occurs in plasminogen deficient mice, the wound area continues to exhibit excessive neutrophil accumulation and collagen deposition after wound closure, providing evidence for an additional requirement for plasminogen in the resolution of inflammation[15]

Summary

Introduction

Wound healing is a fundamental and complex physiologic process that proceeds in overlapping, sequential steps[1]. Recent studies from our group have demonstrated a novel key role for plasminogen in wound healing: plasminogen bound to macrophages and neutrophils is transported to the wound area, where the level of plasminogen is increased locally. This leads to the induction of intracellular signaling and cytokine release[18]. The recruitment of immune cells to cutaneous wounds is not affected by plasminogen deficiency[15,18] and the role of plasminogen in the initial stages of inflammation is predominantly induction of intracellular signaling. Reepithelialization eventually occurs in plasminogen deficient mice, the wound area continues to exhibit excessive neutrophil accumulation and collagen deposition after wound closure, providing evidence for an additional requirement for plasminogen in the resolution of inflammation[15]

Methods

Results

Conclusion