Regulation of Macrophage Polarization and Wound Healing

Background: Macrophages (M phi s) participate in wound healing by coordinating inflammatory and angiogenic processes. M phi s respond to environmental cues by adopting either "classically'' activated (M1) proinflammatory or "alternatively'' activated (M2a, M2b, M2c, M2d) wound healing phenotypes. The Problem: M phi polarization is essential for wound healing and aberrations in this process are linked to several pathologies. It is important to elucidate molecular mechanisms underlying M phi polarization. Basic/Clinical Science Advances: M phi s are categorized as proinflammatory (M1) or anti-inflammatory/wound healing (M2). M1 M phi s are observed in initial tissue damage responses, are induced by exogenous pathogen-associated molecular patterns or endogenous damage-associated molecular patterns, and exhibit increased phagocytosis and pro-inflammatory cytokine production, facilitating innate immunity and wound debridement. M2 M phi s predominate later in repair, express vascular endothelial growth factor, transforming growth factor beta, and interleukin 10 (IL-10), are activated by varied stimuli, assist in the resolution of inflammation, and promote tissue formation and remodeling. Recent work has characterized a novel "M2d'' phenotype resulting from adenosine-dependent "switching'' of M1 M phi s that exhibits a pattern of marker expression that is distinct from canonical IL-4/IL-13-dependent M2a M phi s. Recent studies have demonstrated important roles for specific transcriptional elements in M1 and M2a M phi polarization, notably members of the interferon regulatory factor family interferon regulatory factor 5 (IRF5) and IRF4, respectively. The role of these IRFs in M2d polarization and wound healing remains to be determined. Clinical Care Relevance: Knowledge of microenvironmental signals and molecular mechanisms that mediate M phi polarization should permit their manipulation to regulate important physiological processes and resolve pathological conditions. Conclusion: Proper M phi polarization is essential to effective wound healing, and distinct phenotypes, such as the angiogenic M2d M phi, may be of critical importance to this process. The IRF5 transcription factor has been shown to play a key role in M1 M phi activation and the Jumonji domain containing-3-IRF4 pathway has been implicated in M2 M phi activation.