New Horizons of Macrophage Immunomodulation in the Healing of Diabetic Foot Ulcers

Abstract

Diabetic foot ulcers (DFUs) are one of the most costly and troublesome complications of diabetes mellitus. The wound chronicity of DFUs remains the main challenge in the current and future treatment of this condition. Persistent inflammation results in chronic wounds characterized by dysregulation of immune cells, such as M1 macrophages, and impairs the polarization of M2 macrophages and the subsequent healing process of DFUs. The interactive regulation of M1 and M2 macrophages during DFU healing is critical and seems manageable. This review details how cytokines and signalling pathways are co-ordinately regulated to control the functions of M1 and M2 macrophages in normal wound repair. DFUs are defective in the M1-to-M2 transition, which halts the whole wound-healing machinery. Many pre-clinical and clinical innovative approaches, including the application of topical insulin, CCL chemokines, micro RNAs, stem cells, stem-cell-derived exosomes, skin substitutes, antioxidants, and the most recent Phase III-approved ON101 topical cream, have been shown to modulate the activity of M1 and M2 macrophages in DFUs. ON101, the newest clinically approved product in this setting, is designed specifically to down-regulate M1 macrophages and further modulate the wound microenvironment to favour M2 emergence and expansion. Finally, the recent evolution of macrophage modulation therapies and techniques will improve the effectiveness of the treatment of diverse DFUs.

Polylactic Acid/Poly(vinylpyrrolidone) Co-Electrospun Fibrous Membrane as a Tunable Quercetin Delivery Platform for Diabetic Wounds

“…Wound healing is a very orderly and highly controlled process that requires the integration of complex cellular and molecular events characterized by distinct but overlapping phases: homeostasis, inflammation, cell proliferation, cell migration, angiogenesis and re-epithelialization [ 64 ]. During the initial phase, the role of macrophages is essential both to eliminate non-functional host cells and bacteria and create a favorable environment for tissue regeneration and repair [ 65 ]. Two distinct types of macrophages can be recognized: M1 macrophages, which function as pro-inflammatory mediators, and M2 macrophages, which act as natural feedback regulators from M1 macrophages.…”

Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p

“…Sustained polarization of M1-type macrophages leads to a prolonged inflammatory response and persistent oxidative stress. 65 Another major reason for the failure of diabetic wounds to heal is redox imbalance due to excessive oxidative stress and decreased antioxidant capacity. 66 The combination of azilsartan and NF-kB inhibitor (Bay11-7082) has been reported to promote apoptosis in hepatocellular carcinoma cells by increasing reactive oxygen species (ROS) production and upregulating oxidation levels.…”

Effects of Intensive Glycemic Control on Serum Exosome miR‐126‐3p and miR‐125b‐1‐3p Levels and Wound Healing in Patients with Diabetic Ulcers

“…Tese researchers showed that maintaining HbA1c levels between 7.0% and 8.0% promotes the healing of diabetic ulcers, and patients with better blood sugar on admission heal rapidly. Previous studies have confrmed that hyperglycemia is not conducive to ulcer healing at any stage, as it weakens the phagocytosis and chemotaxis of neutrophils, hinders the synthesis of collagen, impedes the migration of keratinocytes, and induces endothelial progenitor cell dysfunction and polarization of M2 macrophages [20][21][22][23]. However, only a few studies have used experimental data to illustrate the positive efect of intensive glycemic control on diabetic ulcers.…”