Background
Macrophages play important roles during wound healing, and delayed healing in diabetics is associated with sustained inflammation. M1 type macrophage is recognized to secrete excessive amount of tumor necrosis factor-alpha (TNF-α) as compared to its M2 counterpart. Objectives: We hypothesized that macrophage polarization is different between diabetic and normal rats during skin wounding and has direct impact on keratinocyte function in the context of re-epithelialization.
Conclusions
In summary, high glucose wound environment harbored more M1 macrophages infiltration, an event that created excess TNF-α micro-environment. TNF-α upregulated TIMP1 expression in keratinocytes and resulted in impaired keratinocyte migration. Taken together, these events contributed to impaired wound healing during diabetic condition, and targeting TNF-α is a potential therapeutic option to improve diabetic wound healing.
Methods
Skin wounds were created in diabetic and control rats. The phenotypes of infiltrating macrophages, the levels of TNF-α, and the rate of wound closure were determined. Using cell model, the effects of M1 type macrophage on keratinocyte migration were evaluated, and the potential regulatory pathways were determined.
Results
The percentage of M1 macrophages and the levels of TNF-α expression were significantly higher in the perilesional area of diabetic rats as compared to control. The condition media (CM) from M1 type macrophage upregulated tissue inhibitor metalloproteinases (TIMP)-1 expression in keratinocytes and significantly reduced keratinocyte migratory capacity. Addition of neutralizing TNF-α antibody to the CM or gene-silencing of TIMP1 in keratinocytes restored the keratinocyte migratory capacity. Treating wounds of diabetic rats with TNF-α antagonist improved the wound healing process. Conclusions: In summary, high glucose wound environment harbored more M1 macrophages infiltration, an event that created excess TNF-α micro-environment. TNF-α upregulated TIMP1 expression in keratinocytes and resulted in impaired keratinocyte migration. Taken together, these events contributed to impaired wound healing during diabetic condition, and targeting TNF-α is a potential therapeutic option to improve diabetic wound healing.