Macrophages in wound healing: activation and plasticity

Abstract

Macrophages are critically involved in wound healing, from dampening inflammation to clearing cell debris and coordinating tissue repair. Within the wound, the complexity of macrophage function is increasingly recognized, with adverse outcomes when macrophages are inappropriately activated, such as in fibrosis or chronic non-healing wounds. Recent advances in in vivo and translational wound models, macrophage-specific deletions and new technologies to distinguish macrophage subsets, have uncovered the vast spectrum of macrophage activation and effector functions. Here, we summarize the main players in wound-healing macrophage activation and function, including cytokines, apoptotic cells, nucleotides and mechanical stimuli. We highlight recent studies demonstrating cooperation between these factors for optimal wound healing. Next, we describe recent technologies such as cell tracking and single-cell RNA-seq, which have uncovered remarkable plasticity and heterogeneity in blood-derived or tissue-resident macrophages and discuss the implications for wound healing. Lastly, we evaluate macrophage dysfunction in aberrant wound healing that occurs in aging, diabetes and fibrosis. A better understanding of the longevity and plasticity of wound-healing macrophages, and identification of unique macrophage subsets or specific effector molecules in wound healing, would shed light on the therapeutic potential of manipulating macrophage function for optimal wound healing.

Keywords: Apoptotic cell; M2 macrophage; Macrophage; Th2 cytokine; resolving macrophage; wound healing.

Figure 1.. Wound healing macrophage activation.

(a) Injury by cuts, chemicals (CCl₄ and bleomycin), helminths or burn injury causes a breach in barrier. (b) The wound healing response is initiated by dying cells which release cytokines (TSLP, IL-25, and IL-33) that activate Th2 cytokine (IL-4/IL-13) producing cells (blue). Innate cells such as neutrophils (orange) are also recruited to kill invading pathogens, and apoptose once the challenge is resolved. (c) M2 macrophages (left) are activated by the Th2 cytokines. Equally important is the activation of resolving macrophages (right) which are activated by phagocytosis of the apoptotic cells resulting from the inflammation. Rather than distinct subsets, both M2 and resolving macrophages represent a continuum of macrophage activation that are influenced by both Th2 cytokines and apoptotic cells.

Figure 2.. Macrophage enhancers and effectors in wound healing and fibrosis.

Wound healing macrophage activation is enhanced by the following surface markers: (a) signaling through the Myo18A receptor; (b) FcγR-mediated signaling by immune complexes; (c) ATP or adenosine binding to purinergic receptors; (d) Mincle surface expression; and intracellular factor; (e) nuclear receptor PPARγ; (f) micro RNA 21. These enhance macrophage effector function to promote wound healing (green), but if excessive, can lead to fibrosis (brown).