Chronic wounds associated with diabetes represent a significant health problem in the United States. Despite the socioeconomic impact of these poorly healing wounds, the underlying causes of impaired healing are not well understood and effective treatments remain elusive. Chronic wounds exhibit a dysregulated inflammatory response, with persistent accumulation of macrophages and inflammatory cytokines. We propose a translational study to address our central hypothesis that an impaired switch from pro-inflammatory to pro-healing macrophage phenotypes contributes to the poor healing responses in diabetic wounds and that inducing macrophages to switch phenotype will improve healing. The study is composed of three Specific Aims: in the first Aim, we will determine whether sustained activity of the inflammasome, a critical control point in the regulation of inflammation, promotes a bias towards the pro-inflammatory macrophage phenotype in wounds of diabetic mice. In the second Aim, we will determine whether impaired activity of the anti-inflammatory peroxisome proliferator- activated receptor-3 pathway blocks the switch from pro-inflammatory to pro-healing Mp phenotypes in wounds of diabetic mice. In the third Aim, we will determine whether the diabetic wound environment impairs the switch from pro-inflammatory to pro-healing Mp phenotypes, which impairs healing of chronic wounds. The proposed experiments will improve knowledge of the role and regulation of macrophage phenotypes in the impaired healing of diabetic wounds. If the experiments support our central hypothesis, future studies will be focused on developing therapies that modulate macrophage phenotype in chronic wounds to induce resolution of inflammation and stimulate healing responses in these hard-to-heal wounds. In addition, we will determine whether monitoring Mp phenotype in chronic wounds can be used to aid in the selection of treatment options that are currently available for targeting inflammation. PUBLIC HEALTH RELEVANCE: Chronic wounds associated with diabetes represent a significant health problem in the United States with millions of patients suffering from these wounds and the associated treatment costing billions of dollars per year. In the proposed research, we will investigate whether impaired macrophage function contributes to poor healing responses in diabetic wounds. Findings from our experiments will provide insight into whether therapies aimed at altering macrophage function can improve healing of diabetic wounds and whether monitoring macrophage function can aid in the selection of treatment options that are currently available for targeting inflammation. The long-term goal of this project is to reduce the socioeconomic burden of chronic diabetic wounds and improve the quality of life of diabetic patients.