Hyperglycemia acts in synergy with hypoxia to maintain the pro-inflammatory phenotype of macrophages

Diabetic foot ulcers (DFUs) are characterized by a chronic inflammation state which prevents cutaneous wound healing, andDFUs 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 downregulatd 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 ones were downregulated. Subsequently, the contribution of hypoxia and hyperglycemia to chronic inflammation and their potential synergic 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. THP-1 cells cultivated in hyperglycemia or normoglycemia, hypoxia and differentiated into macrophages by PMA. Macrophages activated by LPS