Macrophage Phenotypes in Normal and Diabetic Wound Healing and Therapeutic Interventions

Macrophage differentiation and polarization are essential players in the success of the wound-healing process. Acute simple wounds progress from inflammation to proliferation/regeneration and, finally, to remodeling. In injured skin, macrophages either reside in the epithelium or are recruited from monocytes. Their main role is supported by their plasticity, which allows them to adopt different phenotypic states, such as the M1-inflammatory state, in which they produce TNF and NO, and the M2-reparative state, in which they resolve inflammation and exhibit a reparative function. Reparative macrophages are an essential source of growth factors such as TGF-beta and VEGF and are not found in nonhealing wounds. This review discusses the differences between macrophage phenotypes in vitro and in vivo, how macrophages originate, and how they cross-communicate with other cellular components in a wound. This review also highlights the dysregulation of macrophages that occurs in nonhealing versus overhealing wounds and fibrosis. Then, the therapeutic manipulation of macrophages is presented as an attractive strategy for promoting healing through the secretion of growth factors for angiogenesis, keratinocyte migration, and collagen production. Finally, Hoxa3 overexpression is discussed as an example of the therapeutic repolarization of macrophages to the normal maturation state and phenotype with better healing outcomes.

Automated summary

Macrophage differentiation and polarization are crucial for successful wound healing. Macrophages exhibit plasticity, allowing them to adopt different functional states, contributing to inflammation resolution and tissue regeneration. Reparative macrophages are a source of growth factors, playing a critical role in wound repair. Dysregulation of macrophages is associated with nonhealing wounds and fibrosis. Therapeutic manipulation of macrophages, such as promoting secretion of growth factors, shows promise in promoting wound healing. The example of Hoxa3 overexpression highlights the potential of repolarizing macrophages as a therapeutic strategy.