Wound macrophages as key regulators of repair: origin, phenotype, and function

Abstract

Recent results call for the reexamination of the phenotype of wound macrophages and their role in tissue repair. These results include the characterization of distinct circulating monocyte populations with temporally restricted capacities to migrate into wounds and the observation that the phenotype of macrophages isolated from murine wounds partially reflects those of their precursor monocytes, changes with time, and does not conform to current macrophage classifications. Moreover, findings in genetically modified mice lacking macrophages have confirmed that these cells are essential to normal wound healing because their depletion results in retarded and abnormal repair. This mini-review focuses on current knowledge of the phenotype of wound macrophages, their origin and fate, and the specific macrophage functions that underlie their reparative role in injured tissues, including the regulation of the cellular infiltration of the wound and the production of transforming growth factor-β and vascular endothelial growth factor.

Figure 1

Blood monocyte and wound macrophage phenotypes in the mouse. Macrophages in wounds originate mainly from circulating monocytes. The figure depicts the two subpopulations of murine blood monocytes that are distinguished by their expression of Ly-6C and chemokine receptors CCR2 and CX3CR1. Ly-6C^highCCR2^high monocytes are recruited into wounds early after injury and are known to produce proinflammatory cytokines and to clear wound debris by phagocytosis. Ly-6C^lowCX3CR1^high monocytes subsequently infiltrate wounds and express TGF-β and VEGF. There is conflicting evidence in the literature as to whether Ly-6C^highCCR2^high cells can become Ly-6C^lowCX3CR1^high in the wound. Functions specifically associated with early or late wound macrophages are linked by a black arrow. Other wound macrophage functions not yet clearly assigned to either macrophage population are indicated with a gray arrow. MHCII, major histocompatibility complex type 2; MR, mannose receptor-1; PMN, polymorphonuclear leukocytes.

Figure 2

Wound macrophage phenotypes. The figure depicts a simplified view of the polarization of macrophages toward classic and alternative activation phenotypes to illustrate the concept that wound macrophages share traits with both phenotypes. As discussed in the text, the phenotype of wound macrophages changes as the wound heals. This temporal variability is represented in the table by color-coded symbols indicating selected phenotypic traits of early versus late wound macrophages. Dash marks signify the phenotype marker is not expressed. Table cells are empty when there are no data to confirm or deny expression. Inducible nitric oxide synthase (iNOS) is expressed by macrophages in sterile rat wounds, in infected murine wounds, and in chronic and infected human wounds. Reactive oxygen species (ROS) are produced through the NADPH-dependent respiratory burst oxidase. Heparin-binding proteins (Ym1 and Ym2) are induced in alternatively activated murine macrophages during helminthic infections. Fizz1 (found in inflammatory zone 1) is also known as hypoxia-induced mitogenic factor or Relm-α. LPS, lipopolysaccharide; MR, mannose receptor-1.