SIRT3 Regulates Macrophage-Mediated Inflammation in Diabetic Wound Repair

Control of inflammation is critical for the treatment of non-healing wounds, but a delicate balance exists between early inflammation that is essential for normal tissue repair and the pathologic inflammation that can occur later in the repair process. This necessitates the development of novel therapies that can target inflammation at the appropriate time during repair. Here, we found that SIRT3 is essential for normal healing and regulates inflammation in wound macrophages post-injury. Under ‘pre-diabetic’ conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation. Further, we found that FABP4 regulates SIRT3 in human blood monocytes and inhibiting FABP4 in wound macrophages decreases inflammatory cytokine expression making FABP4 a viable target for the regulation of excess inflammation and wound repair in diabetes. Using a series of ex vivo and in vivo studies with genetically engineered mouse models, as well as diabetic human monocytes, we demonstrate that FABP4 expression is epigenetically upregulated in diabetic wound macrophages and, in turn, diminishes SIRT3 expression thereby promoting inflammation. These findings have significant implications for controlling inflammation and promoting tissue repair in diabetic wounds.