Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing

Abstract

Macrophages and inflammation play a beneficial role during wound repair with macrophages regulating a wide range of processes, such as removal of dead cells, debris and pathogens, through to extracellular matrix deposition re-vascularisation and wound re-epithelialisation. To perform this range of functions, these cells develop distinct phenotypes over the course of wound healing. They can present with a pro-inflammatory M1 phenotype, more often found in the early stages of repair, through to anti-inflammatory M2 phenotypes that are pro-repair in the latter stages of wound healing. There is a continuum of phenotypes between these ranges with some cells sharing phenotypes of both M1 and M2 macrophages. One of the less pleasant consequences of quick closure, namely the replacement with scar tissue, is also regulated by macrophages, through their promotion of fibroblast proliferation, myofibroblast differentiation and collagen deposition. Alterations in macrophage number and phenotype disrupt this process and can dictate the level of scar formation. It is also clear that dysregulated inflammation and altered macrophage phenotypes are responsible for hindering closure of chronic wounds. The review will discuss our current knowledge of macrophage phenotype on the repair process and how alterations in the phenotypes might alter wound closure and the final repair quality.

Keywords: chronic venous disease; chronic wound; diabetes; fibrosis; macrophage; monocyte; wound healing.

Figure 1

M1 and M2 polarisation of macrophages. Monocytes can be classically or alternatively activated to form M1 and M2 macrophages respectively. M1 macrophages can also differentiate into M2 macrophages through local cues and after efferocytosis. The M1 phenotype is pro-inflammatory, phagocytic and bactericidal, while the M2 macrophages act to switch off inflammation and regulate re-vascularisation and wound closure.

Figure 2

The M1 to M2 switch is dysregulated in chronic wounds and, unlike in acute wounds, macrophages are unable to phagocytose neutrophils. (A) In the early inflammatory stage of an acute wound, macrophages phagocytose spent neutrophils. In the later stages, having performed this role, macrophages switch phenotype and are predominantly M2 macrophages; (B) In a chronic wound, macrophages are predominantly M1 that are unable phagocytosis spent neutrophils. This leads to the recruitment of more macrophages and an increase in inflammation.