UC Davis

The skin is the largest organ and serves as a protective barrier for the host and maintains homeostatic functions. In the event of an injury, the integrity of the skin is compromised, and the body initiates the wound healing process to restore the original architecture and function of the skin. Wound healing is made up of three main phases: inflammatory, proliferative, and remodeling. The immune response is crucial for the entirety of the wound healing process. Neutrophils and macrophages provide a defensive line for the injured skin while clearing out cellular debris. Lymphocytes, monocytes, dendritic cells, and macrophages produce and secrete growth factors that induce the expansion and recovery of skin-resident cells. Furthermore, macrophages express metalloproteinases that are involved in the remodeling of the skin’s extracellular matrix. For wound healing to be efficient, the three processes, and the subsequent immune responses, must be tightly regulated and any perturbations will result in impaired healing. Burn injuries are severe cutaneous wounds that are characterized by an intense and prolonged inflammation. Hence, burns are often slow to heal, leading to increased hospitalization times, increased healthcare costs, and a lower quality of life for the patient. While it is intuitive to believe that reducing the local wound inflammation would enhance burn wound healing, it is important to note that inflammatory responses are required for proper healing to occur and that excessively reducing inflammation can lead to other perturbations in wound healing. Therefore, understanding the intricacies of the wound healing processes and the immune responses are necessary to develop novel therapeutic strategies. Despite the recent advances in wound care, much work is still needed to fully delineate the mechanisms that orchestrate the processes of tissue repair after burn injury. While it is well known that burn wounds exhibit an intense inflammatory phase, it is unclear which mediators are the major players in the local responses at the burn site, which sort of the effects they exert, and which biological pathways they are derived from. In this dissertation, I will begin with a detailed introduction on the dynamics of the skin’s immune system and how skin-resident and peripheral immune cells contribute to the homeostasis, defense, and repair of the skin. I will also explain the cellular structure of the skin and the roles they have in maintaining health of the organ. For my dissertation work, I examined the roles of the B2AR and 5-LO pathways in burn wound healing. I performed experiments investigating the role of B2AR signaling in a murine burn injury model by employing bone marrow chimeric mice in which the B2AR was genetically deleted in skin-resident cells, immune cells, or globally. We found that skin-resident B2AR signaling controls re-epithelialization and angiogenesis but does not affect wound-infiltrating immune populations. I found that genetic deletion of 5-LO resulted in enhanced wound healing during the early stages after burn injury, which was associated with decreased wound inflammation and keratinocyte proliferation. Furthermore, I examined the cysteinyl leukotriene (cysLT) branch of the 5-LO pathway and found that inhibition of cysLT activity resulted in delayed burn wound healing that was associated with a perturbed proliferative phase.