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SIRT3 Regulates Macrophage-Mediated Inflammation in Diabetic Wound Repair
Anna M Boniakowski1, Aaron D denDekker1, Frank M Davis1
1Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
Abstract:
Control of inflammation is critical for the treatment of nonhealing 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 after injury. Under prediabetic conditions, SIRT3 was decreased in wound macrophages and resulted in dysregulated inflammation. In addition, we found that FABP4 regulates SIRT3 in human blood monocytes, and inhibition of 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 and diabetic human monocytes, we showed 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.
Insights
Scientists discovered that decreased SIRT3 in diabetic wound macrophages causes inflammation. Targeting FABP4 can restore SIRT3, reduce inflammation, and improve healing in diabetic wounds.
Area of Science:
- Cell Biology
- Immunology
- Wound Healing Research
Background:
- Controlling inflammation is crucial for nonhealing wound treatment.
- A balance between early and pathologic inflammation is essential for tissue repair.
- Novel therapies are needed to target inflammation during specific repair phases.
Purpose of the Study:
- To investigate the role of SIRT3 in wound healing and macrophage inflammation.
- To explore the link between prediabetic conditions, SIRT3, and inflammation.
- To identify FABP4 as a potential therapeutic target for diabetic wound repair.
Main Methods:
- Utilized genetically engineered mouse models and diabetic human monocytes.
- Conducted ex vivo and in vivo studies.
- Examined epigenetic regulation of FABP4 and its effect on SIRT3 expression in macrophages.
Main Results:
- SIRT3 is essential for normal wound healing and regulates macrophage inflammation.
- Prediabetic conditions led to decreased SIRT3 and dysregulated inflammation in wound macrophages.
- FABP4 regulates SIRT3 in monocytes; its inhibition reduced inflammatory cytokine expression.
- Epigenetic upregulation of FABP4 in diabetic wound macrophages diminished SIRT3, promoting inflammation.
Conclusions:
- SIRT3 plays a critical role in regulating inflammation during wound repair.
- FABP4 is epigenetically upregulated in diabetic wound macrophages, suppressing SIRT3 and increasing inflammation.
- Inhibiting FABP4 presents a viable therapeutic strategy to control inflammation and enhance tissue repair in diabetic wounds.
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