Macrophage-mediated inflammation in diabetic wound repair

Abstract

Non-healing wounds in Type 2 Diabetes (T2D) patients represent the most common cause of amputation in the US, with an associated 5-year mortality of nearly 50%. Our lab has examined tissue from both T2D murine models and human wounds in order to explore mechanisms contributing to impaired wound healing. Current published data in the field point to macrophage function serving a pivotal role in orchestrating appropriate wound healing. Wound macrophages in mice and patients with T2D are characterized by a persistent inflammatory state; however, the mechanisms that control this persistent inflammatory state are unknown. Current literature demonstrates that gene regulation through histone modifications, DNA modifications, and microRNA can influence macrophage plasticity during wound healing. Further, accumulating studies reveal the importance of cells such as adipocytes, infiltrating immune cells (PMNs and T cells), and keratinocytes secrete factors that may help drive macrophage polarization. This review will examine the role of macrophages in the wound healing process, along with their function and interactions with other cells, and how it is perturbed in T2D. We also explore epigenetic factors that regulate macrophage polarization in wounds, while highlighting the emerging role of other cell types that may influence macrophage phenotype following tissue injury.

Keywords: Diabetes; Epigenetics; Inflammation; Macrophage; Phenotype; Wound.

Fig. 1.

Gene regulation enzymes associated with inducing macrophage polarization. Histone modifications, DNA modifications, and microRNAs associated with influencing macrophage phenotype. Histone deacetylase (HDAC); Jumonji domain-containing protein (JMJD); Mixed-lineage leukemia (MLL); SET domain bifurcated (SETDB); SET and MYN domain (SMYD); Males-absent on the first (MOF); DNA methyltransferases (DNMT).

Fig. 2.

Cellular regulation of macrophage phenotype in the wound microenvironment. Following injury infiltrating immune cells and structural cells within the wound microenvironment secrete factors that influence macrophage polarization.