**1. Introduction**

Diabetes is a metabolic disease that affects over 300 million people worldwide [1]. Diabetes is characterized by high blood glucose levels due to inadequate amounts of insulin produced and secreted by pancreatic beta cells, plus the loss of sensitivity to insulin in peripheral tissues [2]. There are two major types of diabetes, type 1 diabetes (T1D) and type 2 diabetes (T2D) [3]. T1D constitutes about 5% of all diabetes and is known as a T-cell mediated autoimmune invasion and destruction of insulin-producing beta cells in the pancreas, characterized by a significantly reduced beta cell mass and a significantly reduced secretion of insulin [4]. T2D accounts for about 90% of diabetes, and results from the failure of beta cells to compensate for the insensitivity of cells in responsive to insulin, which is called insulin resistance [5].

Diabetic patients can develop severe complications due to impairment in cell proliferation, differentiation, migration, immune responses, angiogenesis, etc., under a sustained hyperglycemic status [6]. Non-healing wounds, or diabetic foot ulcers (DFUs), are one of the most severe diabetic complications, and represent the leading cause of amputations, with an associated greater than 50% 5-year mortality [7]. Correspondingly, the treatment of DFUs comprises the highest annual US medical expenditure for any diagnosis [8]. Therefore, great effort has been made to understand the pathological processes during diabetic wound healing and to create novel therapies.

During the study of the mechanisms underlying diabetes-related impaired wound healing, accumulating evidence suggests that macrophages play a pivotal role in orchestrating proper wound healing [9]. In the early stages of normal wound healing, macrophages polarize to an M1-like phenotype, whereby they remove pathogens, dead cells and debris, and promote inflammation through secreting pro-inflammatory cytokines [10]. Later in the repair process, macrophages transition to more of an M2-like phenotype to resolve the inflammation and secrete trophic factors that promote the proliferation, differentiation and migration of fibroblasts, keratinocytes, mesenchymal cells and vascular endothelial cells, leading to tissue regeneration, neovascularization and wound repair [10]. These wound macrophages originate from different sources and interact with several other cell types through which they develop diverse functions to properly and efficiently assist with the repair process [11]. It is noteworthy that in diabetes there are alterations in the baseline function of macrophages, as well as the corresponding phenotypic changes in macrophages during the wound healing process [10]. Early in wound healing macrophages are responsible for the initiation and progression of inflammation and removal of pathogens, dead cells and debris. However, at later stages, macrophages instead contribute to the resolution of inflammation, reorganization of extracellular matrices (ECM), re-epithelialization, angiogenesis, cell and tissue regeneration and tissue remodeling through secreting a number of factors at late stages [12]. In a normal healthy situation, macrophages initially polarize to a pro-inflammatory M1 subtype to assist in the early stages of wound healing but then re-polarize to an alternative anti-inflammatory M2 subtype to assist in the later stages of wound healing [13]. Interestingly, diabetes leads to impairment of the M1-to-M2 transition in the later stages of wound healing, resulting in sustained inflammation and compromised cell proliferation, differentiation and migration, abnormal immune responses and inadequate angiogenesis [14]. Therefore, different strategies have been generated to target macrophages in order to reverse this pathologic inflammation during diabetic wound healing through modulating macrophage polarization [15]. In this book chapter, we discuss the role of macrophages in normal wound healing and their impairments during diabetic wound healing. We also discuss the present approaches to enhancing the repair of DFUs through targeting macrophages.
