Abstract
Monocytes and lymphocytes play a key role in physiologic wound healing and might be involved in the impaired mechanisms observed in diabetes. Skin wound macrophages are represented by tissue resident macrophages and infiltrating peripheral blood recruited monocytes which play a leading role during the inflammatory phase of wound repair. The impaired transition of diabetic wound macrophages from pro-inflammatory M1 phenotypes to anti-inflammatory pro-regenerative M2 phenotypes might represent a key issue for impaired diabetic wound healing. This review will focus on the role of immune system cells in normal skin and diabetic wound repair. Furthermore, it will give an insight into therapy able to immuno-modulate wound healing processes toward to a regenerative anti-inflammatory fashion. Different approaches, such as cell therapy, exosome, and dermal substitute able to promote the M1 to M2 switch and able to positively influence healing processes in chronic wounds will be discussed.
Highlights
Diabetes is a predominant disease worldwide, with patients developing a wide variety of chronic complications, including Diabetic Foot (DF), characterized by non-healing ulcers [1]
Interleukins IL-4 and IL-13 induce the anti-inflammatory type M2. Depending on their activation in vitro, M2 macrophages have been further classified into different subpopulations: The M2a is activated by IL-4 or IL-13; M2b is activated by immune complexes, IL-1β, or LPS; M2c is activated by IL-10 and TGF-β; and M2d predominantly secretes IL-10 and vascular endothelial growth factor or VEGF [30]
This paper shows that in an in vitro human co-culture model, pro-inflammatory M1 macrophages are essential to initiating sprouting angiogenesis via the targeted delivery of proangiogenic cytokines and VEGF and that a temporal phenotypic switching to M2 is a requirement to permit appropriate later vessel remodeling and regression [43]
Summary
Diabetes is a predominant disease worldwide, with patients developing a wide variety of chronic complications, including Diabetic Foot (DF), characterized by non-healing ulcers [1]. Extensive research tries to better highlight the diabetic wounds pathophysiology and, in particular, the role of inflammatory cell populations within the wound and how they are modified in diabetes [4] Different cell populations such as mast cells, neutrophils, lymphocytes, monocytes, macrophages, keratinocytes, fibroblasts, and endothelial cells contribute to different stages of skin wound healing [5]. Studies in monocyte/macrophage-depleted mice show that these cells are essential for normal wound healing, collagen deposition, angiogenesis, and wound closure [12,13]. Recent data suggest an unexpected key role of Treg in the angiogenesis and tissue regeneration in diabetic wound [23] It has been recognized the influence of immune system on the regenerative therapies, according to a so-called “immune-centric revolution” or “macrophage centered approach [24–26]. Examples of several different approaches that have been taken toward promoting anti-inflammatory (M2-like) macrophages to heal chronic wounds will be discussed
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