The role of platelet-macrophage interactions in inflammation and wound healing Public Deposited

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  • March 21, 2019
Creator
  • Scull, Christopher Matthew
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
Abstract
  • During the normal response to injury, platelets and the proteins of the coagulation cascade achieve hemostasis by forming a platelet-rich clot. Platelets are later removed from the wound site by macrophages. This phase of wound healing, known as the late inflammatory phase, also involves the release of many cytokines which amplify the leukocyte response. This inflammatory phase is dysfunctional in patients who suffer from impaired wound healing, which often predisposes them to infection and/or increased time to wound closure. A better understanding of how inflammation resolves during normal wound healing may help identify new methods of intervention for patients who suffer from impaired wound healing. The overall goal of this dissertation is to better define the role of platelet-macrophage interactions in the resolution of inflammation and wound healing. We hypothesize that platelet-macrophage interactions enhance the inflammatory response during cutaneous wound healing. The first part of this work characterizes the mechanisms that regulate macrophage phagocytosis of autologous platelets, including analysis of common surface proteins on the platelets and macrophages and their potential role for internalization of platelets. Using in vitro phagocytosis assays and analysis by microscopy, we analyzed the conditions necessary for platelet uptake, the role of platelet activation in this process, and the role of sulfated polysaccharides in inhibiting this process. The second part of this work focuses on the inflammatory consequences of platelet-macrophage interactions. Cytokines secreted from resting and LPS-activated macrophages were analyzed during co-incubation of macrophages with either apoptotic cells or activated platelets. We also tested the in vivo role of one particular cytokine, IL-23, in cutaneous wound healing using both IL-23 knockout mice and their wild-type littermates. The overall conclusions of this work suggest that macrophage phagocytosis of autologous platelets correlates with platelet activation, yet occurs independently of platelet surface P-selectin and phosphatidylserine. Secondly, platelet uptake enhances macrophage activation and pro-inflammatory cytokine secretion, which is in sharp contrast to the macrophage response following phagocytosis of apoptotic cells. Finally, in vivo studies suggest that in the absence of IL-23 expression, wound healing is slightly impaired.
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  • In Copyright
Note
  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pathology and Laboratory Medicine."
Advisor
  • Fischer, Thomas H.
Degree granting institution
  • University of North Carolina at Chapel Hill
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Place of publication
  • Chapel Hill, NC
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  • Open access
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