The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes

Abstract

Macrophages play key roles in all phases of adult wound healing, which are inflammation, proliferation, and remodeling. As wounds heal, the local macrophage population transitions from predominantly pro-inflammatory (M1-like phenotypes) to anti-inflammatory (M2-like phenotypes). Non-healing chronic wounds, such as pressure, arterial, venous, and diabetic ulcers indefinitely remain in inflammation-the first stage of wound healing. Thus, local macrophages retain pro-inflammatory characteristics. This review discusses the physiology of monocytes and macrophages in acute wound healing and the different phenotypes described in the literature for both in vitro and in vivo models. We also discuss aberrations that occur in macrophage populations in chronic wounds, and attempts to restore macrophage function by therapeutic approaches. These include endogenous M1 attenuation, exogenous M2 supplementation and endogenous macrophage modulation/M2 promotion via mesenchymal stem cells, growth factors, biomaterials, heme oxygenase-1 (HO-1) expression, and oxygen therapy. We recognize the challenges and controversies that exist in this field, such as standardization of macrophage phenotype nomenclature, definition of their distinct roles and understanding which phenotype is optimal in order to promote healing in chronic wounds.

Keywords: chronic wounds; inflammation; macrophages; skin regeneration; wound healing.

Figure 1

Monocyte-Macrophage Recruitment and Differentiation in Wounds. The mechanism of monocyte recruitment and macrophage differentiation during dermal wound healing can vary depending on spatiotemporal cues. A few models are presented: (1) Classical monocytes in the circulation are primed to differentiate into M1 macrophages following extravasation. In the wound microenvironment, they respond to spatiotemporal cues and can differentiate into any of the M2-like phenotypes, which can transdifferentiate into one another. For brevity, M2a, b, c and d phenotypes are also categorized as M2-like in the remaining processes. (2) Classical monocytes can differentiate into M1 macrophages in the wound. In contrast to the first model, in this panel, macrophages retain the M1 phenotype without further differentiating to M2-like macrophages. Similarly, non-classical monocytes are primed to differentiate into M2-like macrophages and can retain this phenotype. This panel suggests that the final macrophage phenotype is predetermined by the starting monocyte phenotype, and an M1/M2 transition does not occur. (3) This model shows that classical monocytes, rather than macrophages, can also persist in the wound environment for several days, and at a later time, differentiate into non-classical monocytes and then M2-like macrophages. Dashes on the blood vessel indicate that monocytes can exit damaged vasculature via micro-hemorrhages. The yellow star-shape represents resident macrophages, which are established during embryonic development. The purple star-shape represents a possible Mhem phenotype in wounds (analogous to that found in atherosclerotic plaques) which breakdowns hemoglobin and releases anti-inflammatory factors.

Figure 2

The Role of Macrophage Phenotypes in Wound Healing. Acute wounds progress through the phases of inflammation, proliferation and remodeling as they heal. In inflammation, pro-inflammatory macrophages are present. Their role is to phagocytose dead cells and bacteria and prepare the wound for healing. In proliferation, pro-wound healing macrophages are present. They secrete factors that aid in angiogenesis, formation of granulation tissue, collagen deposition, and reepithelialization. In remodeling, pro-resolving macrophages aid in breakdown of the provisional granulation tissue to allow for maturation of collagen and strengthening of the newly regenerated skin. Below the diagrams are the general roles and timing of different macrophage phenotypes during the wound healing process. Differences between in vivo and in vitro classifications are separated by the dashed line, however similar roles can be seen between many of the phenotypes. The timing is an estimate based on the role of each phenotype, and has not been experimentally confirmed.