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

• Published in: PloS one 2019-08, Vol.14 (8), p.e0220577-e0220577
• Main Authors: Morey, Mangesh, O'Gaora, Peadar, Pandit, Abhay, Hélary, Christophe
• Format: Article
• Language: English
• Subjects: Amputation; Angiogenesis; Anopheles; Anoxia; Apoptosis; Apoptosis - physiology; Biochemistry; Biology and Life Sciences; Bone morphogenetic proteins; Cell activation; Cell Differentiation - drug effects; Cell Hypoxia - physiology; Cell Line, Tumor; Chemokines; Complications and side effects; Cytokines; Cytokines - metabolism; Diabetes; Diabetes mellitus; Diabetic foot; Diabetic Foot - metabolism; DNA microarrays; Endocrinology and metabolism; Foot diseases; Gene expression; Genes; Genetic aspects; Genotype & phenotype; Glucose; Glucose - administration & dosage; Human health and pathology; Humans; Hyperglycemia; Hyperglycemia - metabolism; Hypoxia; Infection; Inflammation; Interleukin 1; Interleukin 6; Interleukin-6 - metabolism; Leg ulcers; Life Sciences; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Medical equipment; Medicine and Health Sciences; Neutrophils; Phagocytosis; Phenotypes; Physical Sciences; Receptors; Risk factors; Synergistic effect; Transforming growth factor-b1; Transforming growth factors; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Ulcers; Up-Regulation - drug effects; Wound care; Wound healing; Wound Healing - physiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0220577

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.