723 High glucose environment induces macrophage M1 polarization that contributes to impaired wounding via reducing keratinocyte migration

Abstract

Diabetes is an important global health issue due to its increasing prevalence and association with serious co-morbidities including impaired wound healing. A hallmark of impaired diabetic healing is suboptimal re-epithelialization, an event that is regulated by infiltrating macrophages. The present study aimed to explore the effects of high glucose environment on macrophage polarization and explore the resulting effect on keratinocyte function using relevant cell and animal models. Our results showed that high glucose environment polarized cultured human macrophages toward classical M1 phenotype as demonstrated by significant upregulation of CCR7 expression. Additionally, condition media from the M1 macrophages significantly decreased human keratinocyte migration via reducing the metalloproteinase 1 (MMP1) expression in keratinocytes by more than 50%. Highly increased tumor necrosis factor-alpha (TNF-a) secretion from the M1 macrophages was responsible for inhibiting MMP1 expression in keratinocytes. These in vitro results were validated in vivo using a diabetic animal model. More specifically, the wound healing was delayed in diabetic rats with prolonged infiltration of M1 macrophages, elevated TNF-a expression in the wound area, and reduced MMP1 expression in the perilesional skin. In summary, our results demonstrated that high glucose environment induced macrophage M1 polarization, an event that leads to TNF-a mediated MMP1 suppression in keratinocytes and results in impaired keratinocyte migration. Restoring the macrophage phenotype and neutralizing elevated TNF-a in the diabetic wound environment are potential strategies to promote better diabetic wound healing in the near future.