The Plasminogen Receptor, Plg‐R_KT, Regulates Inflammation and Fibrinolysis During Wound Healing

Abstract

Plasminogen is a key regulatory protein that functions to both promote fibrinolysis and to potentiate the inflammatory response during wound healing. Here we have tested the hypothesis that the novel plasminogen receptor, Plg‐RKT, regulates distinct steps in the wound healing process. Method Full‐thickness standardized burn wounds (1 cm in diameter) were induced in mice and the wound area was quantified at different time points. Wound tissue was subjected to qPCR and ELISA for cytokine expression and immunohistochemistry and Western blotting for fibrin deposition and leukocyte recruitment. Results From day 9 after injury, healing in Plg‐RKT−/− mice was significantly delayed compared with healing in Plg‐RKT+/+ littermates. Expression of cytokines, IL‐1β, CCL‐20, TNFα, and IL‐10 was dysregulated in Plg‐RKT−/− tissue although no genotype‐dependent differences in recruitment of macrophages or neutrophils to the wound area were detected. Consistent with dysregulated cytokine expression, a significant delay in wound healing during the proliferation phase (days 9 and 10) was observed in wound tissue from mPlg‐RKT−/− mice in which Plg‐RKT was specifically deleted in myeloid cells. Regarding fibrinolysis, fibrin clearance was significantly impaired in Plg‐RKT−/− wound tissue. Genetic reduction of fibrinogen levels of Plg‐RKT−/− mice to 50% completely abrogated the effect of Plg‐RKT deletion on healing of burn wounds and, remarkably, effects of Plg‐RKT deletion on cytokine expression were modulated by the reduction in fibrinogen levels. In conclusion, Plg‐RKT plays a key role in wound healing by regulating both fibrinolysis and the inflammatory response and fibrin plays a role in regulating Plg‐RKT function on myeloid cells. Support or Funding Information United States National Institutes of Health grants HL 081046 to LAM and HL 149511 to LAM and RJP and Merit Review Award #5I01BX002026 from the U.S. Department of Veterans Affairs to RJP.