Role of skin injury-induced inflammation in wound healing

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PROJECT SUMMARY Chronic skin wounds like diabetic foot ulcers (DFU) are a serious medical problem in Veterans. Up to one third of patients with diabetes develop DFU, a leading cause of lower leg amputations as well as skin and bone infections and an independent risk factor for death. As current therapies are limited and often ineffective, there is a critical need to better understand pathogenesis in order to identify new and improved therapies for chronic wounds in diabetes and other disease states. Repetitive skin injury and skin inflammation are independently implicated in DFU pathogenesis; however, gaps in knowledge exist regarding how skin injury and inflammation interact in diabetic (and healthy) skin and how this interaction could impair wound healing. We recently identified an inflammatory response that is activated by mechanical skin injury and refer to this as the skin injury-induced inflammatory response. Our preliminary data suggest the IL-1 signaling initiates this response and contributes to DFU pathogenesis. The objective of this project is to determine how IL-1 signaling regulates the skin injury-induced inflammatory response and contributes to normal wound healing as well as impaired wound healing in a mouse model of type 2 diabetes. Our central hypothesis is IL-1 signaling activates the skin injury-induced inflammatory response and promotes scarring during normal and diabetic wound healing and that dysregulated IL-1 signaling amplifies inflammation and impairs diabetic wound healing. Aim 1 will determine the role of keratinocyte-derived IL-1 and IL-1 receptor signaling during normal skin wound healing in mice and determine if disrupting IL-1 signaling reduces scarring and enhances normal wound healing. Aim 2 will examine the role of IL-1 and IL-1 receptor signaling in a mouse model of type 2 diabetes mellitus and determine if disrupting IL-1 signaling enhances diabetic wound healing. Aim 3 will use ex vivo-cultured human skin from healthy and diabetics subjects to define the contributions of IL-1 and blood sugar control to the skin injury-induced inflammatory response transcriptome in whole skin tissue and at the level of single cells. This project will define the role of IL-1/IL-1R1 axis activation on skin injury-induced inflammation in healthy and diabetic human and mouse skin and the consequences of IL-1/IL-1R1 signaling during wound healing. This coupled with identification of new molecular targets during these studies will facilitate further research and development of new therapies to promote wound healing in diabetes and other disease states.