Macrophages in Skin Wounds: Functions and Therapeutic Potential

Abstract

Macrophages regulate cutaneous wound healing by immune surveillance, tissue repair and remodelling. The depletion of dermal macrophages during the early and middle stages of wound healing has a detrimental impact on wound closure, characterised by reduced vessel density, fibroblast and myofibroblast proliferation, delayed re-epithelization and abated post-healing fibrosis and scar formation. However, in some animal species, oral mucosa and foetal life, cutaneous wounds can heal normally and remain scarless without any involvement of macrophages. These paradoxical observations have created much controversy on macrophages' indispensable role in skin wound healing. Advanced knowledge gained by characterising macrophage subsets, their plasticity in switching phenotypes and molecular drivers provides new insights into their functional importance during cutaneous wound healing. In this review, we highlight the recent findings on skin macrophage subsets, their functional role in adult cutaneous wound healing and the potential benefits of targeting them for therapeutic use.

Keywords: NF-κB; chronic wounds; cytokine signalling; inflammation; macrophage; wound healing; wound regeneration.

Figure 1

(A) Signalling crosstalk between macrophages (Mϕ) with other cell types during the inflammatory phase of cutaneous wound healing. (i) Nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) is major regulator of pro-inflammatory cytokines in macrophages (e.g., tumour necrosis factor alpha (TNF-α), interferon (IFN)-γ and interleukin (IL)-1β). (ii) Neutrophils produce nitric oxide (NO) and reactive oxygen species (ROS) to prevent pathogen colonisation. (iii) (C-C motif) ligand 2 (CCL2) released by tissue-resident cells recruits Ly6C^Hi monocytes into the wound during the inflammatory phase. (iv) Ly6C^Hi monocytes differentiate into (C-C motif) chemokine receptor 2 (CCR2⁺)Ly6C^Hi Mϕ, releasing pro-inflammatory cytokines. (v) Macrophages help to remove pathogen via phagocytosis. (vi) Nrf2 mediates keratinocytes’ CCL2 production which is required for CCR2⁺ monocyte recruitment. (B) Signalling crosstalk between macrophages and other cell types during the proliferation phase of cutaneous wound healing. (i) (C-X3-C motif) chemokine receptor 1 (CX3CR1)^Lo Mϕ guide nerve sprouting during wound repair and acquire high CX3CR1 expression progressively after injury. (ii) Efferocytosis of neutrophils induce macrophage anti-inflammatory phenotype switch. (iii) CX3CR1⁺Ly6C^Lo Mϕ (pro-healing phenotype) produce anti-inflammatory cytokines and growth factors, such as vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP) and transforming growth factor (TGF)-β that help to dampen inflammation and promote angiogenesis and wound contraction. (iv) TGF-β is a crucial regulator of fibroblasts/myofibroblasts. (v) Platelet-derived growth factor C (PDGF-C) and IGF-1-producing CD301b⁺ Mϕ promote the proliferation of adipocyte-derived myofibroblasts during wound healing. (vi) Infiltrating F4/80⁺ macrophages produce epithelial growth factor (EGF) to promote keratinocyte re-epithelisation. (vii) Insulin-like growth factor 1 (IGF-1) from dendritic epidermal T cells (DETC) also helps to promote re-epithelisation, while IL-17A from γδT cells and IL-1β/IL23 produced by keratinocytes negatively regulate DETC IGF-1 production. (C) Macrophages regulate vessel regression during the remodelling phase of cutaneous wound healing. (i) Macrophages remove apoptotic endothelial cells via phagocytosis. (ii) Emerging evidence suggests that endothelial cells might undergo endothelial-to-mesenchymal transition (EndMT) during cutaneous wound healing.