633 Regulation of IFN kappa in keratinocytes of diabetic wounds

Abstract

Chronic inflammation in non-healing wounds of Type 2 Diabetes (T2D) patients represents the most common cause of amputation and mortality. Thus, a critical need still exists for understanding the wound healing defects in T2D to develop better targeted therapies. Current data points to a role for keratinocytes in orchestrating appropriate wound healing and demonstrates that wound keratinocytes in T2D are dysfunctional; however, the mechanisms that regulate this dysfunction is unclear. Interferon kappa (IFNk), a type I IFN primarily produced by keratinocytes, has been shown to play an important role in other chronic skin diseases. Thus, this project explores the role of keratinocyte-mediated IFNk in wound repair. To examine IFNk expression, we utilized skin samples from T2D patients and mice, along with their respective controls. We found that IFNk expression is impaired in both human and murine models of T2D wounds. This attenuation is particularly noted in basal keratinocytes. Interestingly, we identified by ChIP PCR the IFNk promoter in T2D keratinocytes has decreased expression of H3K4me3 compared to control in a mixed lineage leukemia (MLL)-dependent manner. To further understand the role of IFNk in wound repair, a wound curve was performed on IFNk KO and WT mice. We show that knockout of IFNk impairs wound healing. Thus, our data suggest IFNk impairs wound healing in T2D patients and this attenuation of IFNk expression in keratinocytes is regulated epigenetically. Continued investigation into the mechanism through which keratinocyte-mediated IFNk impairs wound healing is key to development of novel treatments for T2D patients.