JAK/STAT Regulation of Macrophage-mediated Inflammation in Diabetic Wound Repair

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PROJECT SUMMARY/ABSTRACT Non-healing wounds in diabetes are the leading cause of lower extremity amputations and are associated with significant morbidity and mortality. Currently, there is an unmet need for more effective therapies, since existing treatments leave nearly 70% of diabetic wounds unhealed. Thus, a critical need exists for understanding the pathophysiology of wound healing and identifying more effective treatment strategies for patients with diabetic wounds. Following injury, monocyte-macrophages are recruited to the wound where they transition from a pro- inflammatory to an anti-inflammatory phenotype; an essential switch that is necessary for tissue repair. However, in diabetic wounds, macrophages fail to transition to an anti-inflammatory, reparative phenotype, thereby leading to an overall pro-inflammatory state that results in impaired wound healing. Although epigenetic mechanisms have been shown to regulate Mφ phenotype in wounds, the regulation of these epigenetic pathways in diabetic wounds remains unknown. Our preliminary data identifies that JMJD3, a histone demethylase that selectively demethylates histone 3 at lysine 27 (H3K27), increases inflammatory gene transcription and is increased in murine and human diabetic wound macrophages. Further, we found that JAK1-STAT3 signaling may regulate Jmjd3 transcription in wound Ms. Considering these findings, we hypothesize that increased JAK1-STAT3 signaling induces Jmjd3 in diabetic wound Ms and upregulates inflammatory gene expression. Further, we postulate that inhibiting JMJD3 or JAK1,3 in diabetic wound Ms improves tissue repair. This hypothesis will be investigated through the following specific aims: 1) To identify the JAK1/STAT3-mediated mechanism(s) that regulate Mφ-specific Jmjd3 expression in normal and diabetic wound tissue and human monocytes. 2) To determine the effects of JAK1,3 and JMJD3 inhibition on diabetic wound Mφ polarization and tissue repair.