Abstract
Diabetic foot ulcers (DFUs) are characterized by a chronic inflammation state which prevents cutaneous wound healing, and DFUs eventually lead to infection and leg amputation. Macrophages located in DFUs are locked in an pro-inflammatory phenotype. In this study, the effect of hyperglycemia and hypoxia on the macrophage phenotype was analyzed. For this purpose, a microarray was performed to study the gene expression profile of macrophages cultivated in a high glucose concentration. Hyperglycemia upregulated the expression of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, chemokines and downregulated the expression of two receptors involved in phagocytosis (CD 36 and Class B scavenger type I receptors). In addition, eleven anti-apoptotic factors were upregulated whereas three pro-apoptotic genes were downregulated. Subsequently, the contribution of hypoxia and hyperglycemia to chronic inflammation and their potential synergistic effect was evaluated on activated THP-1 derived macrophages. A long term post activation effect (17 hours) was only observed on the upregulation of pro-inflammatory cytokines when hypoxia was combined with a high glucose concentration. In contrast, hyperglycemia and hypoxia did not have any effect on wound healing molecules such as TGF-β1. Taken together, the results show that hyperglycemia acts in synergy with hypoxia to maintain a chronic inflammation state in macrophages.
Highlights
Diabetic foot ulcers are the most common, painful and crippling complications of diabetes mellitus [1]
THP-1 cells were cultivated for 6 weeks either in hyperglycemia (4.5g/L glucose) or Hyperglycemia acts in synergy with hypoxia to maintain the pro-inflammatory phenotype of macrophages normoglycemia (1g/L glucose) before differentiation
3.1 Gene expression profile of macrophages cultivated in hyperglycemia and hypoxia
Summary
Diabetic foot ulcers are the most common, painful and crippling complications of diabetes mellitus [1]. These pathologies affect 3% of the diabetic population each year and this figure is expected to rise due to the increasing prevalence of diabetes [2]. In their lifetime, diabetic people have a 25% risk of developing a diabetic foot ulcer (DFU) [3]. 85% of amputations are the consequence of DFU [4].The major underlying pathologies that cause DFU are peripheral neuropathy, vascular diseases and anatomic.
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