Role of Macrophages in Wound Healing

Abstract

Monocytes/macrophages are key components of the body's innate ability to restore tissue function after injury. In most tissues, both embryo-derived tissue-resident macrophages and recruited blood monocyte-derived macrophages contribute to the injury response. The developmental origin of injury-associated macrophages has a major impact on the outcome of the healing process. Macrophages are abundant at all stages of repair and coordinate the progression through the different phases of healing. They are highly plastic cells that continuously adapt to their environment and acquire phase-specific activation phenotypes. Advanced omics methodologies have revealed a vast heterogeneity of macrophage activation phenotypes and metabolic status at injury sites in different organs. In this review, we highlight the role of the developmental origin, the link between the wound phase-specific activation state and metabolic reprogramming as well as the fate of macrophages during the resolution of the wounding response.

Figure 1.

Schematic overview of different stages of wound healing. Shown are the sequential and overlapping phases of the injury response. Macrophages play an important role in all stages; their function changes in the early stages (hemostasis, inflammation) compared with the latter ones (proliferation, remodeling) because of their high functional plasticity and communication with different cell subsets. During hemostasis and inflammation, macrophages together with polymorphonuclear neutrophils (PMNs) ensure bacterial clearance engaging Toll-like receptors (TLRs) to recognize and internalize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). During the transition of the inflammatory phase into the proliferative phase, macrophages together with other wound cells release multiple growth factors (in orange), stimulating the proliferation of stromal and parenchymal cells and the production of extracellular matrix (ECM) components to ensure the restoration of the original tissue. Growth factors: epidermal growth factor (EGF), transforming growth factor β (TGF-β), fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and placental growth factor (PLGF).

Figure 2.

Origin of macrophages during homeostasis and inflammation. Under homeostatic conditions, organs contain tissue-resident macrophages that originate from both the yolk sac/liver during embryogenesis and from bone marrow–derived circulating monocytes postnatally. Upon injury, the recruitment of blood monocytes will quickly outweigh the resident populations and will constitute the main source of proinflammatory macrophages at the wound site. Reprogramming of inflammatory toward repair macrophages is required for resolution and healing.

Figure 3.

Early- and late-stage reprogramming of macrophages. Macrophages are highly versatile cells being able to ensure both proinflammatory and pro-resolution functions in the tissues depending on the environmental stimuli. Proinflammatory macrophages are characterized as highly glycolytic cells, thus producing lactate that will lower the extracellular pH and contribute to acidosis. They are characterized by an increased production of mitochondrial reactive oxygen species (mtROS), stabilizing transcription factor hypoxia inducible factor 1α (HIF1α) that enables the production of angiogenic factors, such as vascular endothelial growth factor A (VEGF-A), and proinflammatory cytokines, such as interleukin 1β (IL-1β), and enhances the use of glucose metabolism. Moreover, proinflammatory macrophages are professional phagocytes ensuring both the removal of apoptotic polymorphonuclear cells (PMNs) and other cell debris and the killing of pathogenic bacteria using Toll-like receptors (TLRs) and nicotinamide adenine dinucleotide phosphate + hydrogen (NADPH) oxidase 2 (NOX2). The recognition of pathogen-associated molecular patterns (PAMPs) will lead to nuclear factor κ light-chain enhancer of activated B-cell (NF-κB) stabilization and the transcription of major proinflammatory cytokines (tumor necrosis factor α [TNF-α], IL-1β, IL-6, interferon γ [IFN-γ], C-C motif chemokine ligand 2 [CCL2]) and mediators (nitric oxide [NO] by inducible NO synthase [iNOS]), sustaining the inflammatory reaction. Pro-resolution macrophages (cluster of differentiation 163⁺ [CD163⁺], CD206⁺, IL-4Rα, arginase 1 high [Arg1^high]) are characterized by an enhanced mitochondrial metabolism, relying mostly on fatty acid (FA) oxidation coupled to oxidative phosphorylation (OXPHOS). They ensure the restoration of tissue integrity by producing anti-inflammatory cytokines (IL-10, TGF-β) tempering the proinflammatory response. Moreover, they produce mediators that stimulate extracellular matrix (ECM) production in fibroblasts and ECM stabilization.