! Impaired wound healing in response to traumatic injury, surgery, or in disease, remains a signi?cant clinical challenge. Macrophages are essential regulators of this process, and are involved in both advancing in?ammation and promoting tissue repair processes. In addition, these cells play a major role in the progression of numerous pathologies including cardiovascular disease, cancer, and the immune response to biomaterial implants. While much is known about how soluble factors including chemokines and cytokines regulate macrophage function, less is understood about how adhesive cues in the extracellular matrix might contribute to macrophage behavior. In this study, we will investigate the role of ?brin, a key component of the provisional extracellular matrix formed during wound healing, in the modulation of macrophage function. We hypothesize that the presentation of ?brinogen within ?brin matrices differentially modulates their interactions with the integrin receptor CD11b and Toll-like receptor-4 (TLR4) to regulate in?ammatory versus anti-in?ammatory signaling. To test our hypothesis, we propose the following aims: (1) To examine the role of CD11b and TLR4 signaling in response to ?brinogen and ?brin using molecular and genetic tools, (2) to investigate how tethering of ?brinogen within ?brin gels alters the mechanical interactions with macrophages, and how these changes result in modulation of macrophage function, and (3) to examine the effect of ?brin(ogen) and macrophage polarization in a full thickness wound model. The long term goal of the proposed work is to better understand regulation of macrophages by the extracellular matrix during wound healing, in order to develop new strategies to control macrophage function in disease.
This work aims to investigate the role of the extracellular matrix on macrophage inflammatory versus repair function during wound healing. Specifically, we are examining the role of provisional extracellular matrix components, fibrin and fibrinogen, on mechanochemical signaling in macrophages. A better fundamental understanding of macrophage biology during wound healing can lead to new therapeutic approaches to control immune-mediated tissue repair.
