Disclosure of the Culprits: Macrophages-Versatile Regulators of Wound Healing.

SIGNIFICANCE: Macrophages are invariably present and tightly regulate all phases of adult wound healing, including inflammation, granulation tissue formation, and matrix deposition with the unavoidable outcome of scar formation. In response to environmental cues, macrophages mount a "classical" pro-inflammatory M1 activation as opposed to the "alternative" M2 phenotype, with wound macrophages having long been viewed as M2 macrophages. RECENT ADVANCES: Recent studies rather point to large temporal and phenotypic variations of wound macrophages subsets. Therefore, a functional classification of macrophages according to wound-healing phases appears to better meet the in vivo complexity. In an ideal but simplistic scenario grossly reflecting normal wound healing, initial tissue injury induces inflammatory M1-like macrophages, which, upon engulfment of apoptotic neutrophils or in response to other inflammation dampening stimuli, switch toward anti-inflammatory M2-like macrophages and further toward growth factor-producing pro-fibrotic M2a-like macrophages. Although not yet documented for skin wounds, a subset of metalloproteinase-producing fibrolytic M2c-like macrophages may contribute to fibrosis resolution. Recent work identified a diversity of novel macrophage phenotypes associated with normal and pathologic wound healing, most of them ranging out of the M1/M2 paradigm. Iron-overloaded M1-like macrophages represent such a novel phenotypic subset driving the non-healing state of chronic venous leg ulcers. CRITICAL ISSUES: Despite growing evidence that macrophage dysfunctions are, at least in part, responsible for pathologic wound healing, including nonhealing wounds and excessive scar formation, these are hardly specifically addressed even by modern therapeutic strategies. FUTURE DIRECTIONS: If characterized in sufficient detail, distinct macrophage subsets and their impaired functions provide ideal targets for improving wound healing.