Immunology of Acute and Chronic Wound Healing

Abstract

Skin wounds greatly affect the global healthcare system, creating a substantial burden on the economy and society. Moreover, the situation is exacerbated by low healing rates, which in fact are overestimated in reports. Cutaneous wounds are generally classified into acute and chronic. The immune response plays an important role during acute wound healing. The activation of immune cells and factors initiate the inflammatory process, facilitate wound cleansing and promote subsequent tissue healing. However, dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wounds. The microenvironment of a chronic wound is characterized by high quantities of pro-inflammatory macrophages, overexpression of inflammatory mediators such as TNF-α and IL-1β, increased activity of matrix metalloproteinases and abundance of reactive oxygen species. Moreover, chronic wounds are frequently complicated by bacterial biofilms, which perpetuate the inflammatory phase. Continuous inflammation and microbial biofilms make it very difficult for the chronic wounds to heal. In this review, we discuss the role of innate and adaptive immunity in the pathogenesis of acute and chronic wounds. Furthermore, we review the latest immunomodulatory therapeutic strategies, including modifying macrophage phenotype, regulating miRNA expression and targeting pro- and anti-inflammatory factors to improve wound healing.

Keywords: acute wound; adaptive immunity; chronic wound; cutaneous wound healing; innate immunity.

Figure 1

Immune system in acute wound healing. Skin-resident macrophages are the first immune cells that respond to injury. When activated by DAMPs, they release cytokines and chemokines to recruit neutrophils and monocytes to the inflammatory site. Monocytes then differentiate into pro-inflammatory M1 macrophages. Mast cells also facilitate monocyte differentiation by secreting monocyte chemoattractant protein-1 (MCP-1). Moreover, mast cells, which are stimulated by keratinocytes, secrete mediators to promote vasodilation that enhance immune cell recruitment. Activated neutrophils release ROS, neutrophil extracellular traps (NETs), cytotoxic granules and other mediators that promote bacterial clearance and tissue re-epithelialization. Pro-healing M2 macrophages contribute to tissue repair and inhibition of inflammation. LCs promote tissue repair, although the precise mechanism is not clear. Various T cells subsets are found in acute wounds and are responsible for bacterial elimination, modulation of immune responses and tissue remodeling.

Figure 2

Immune system in chronic wound healing. Common features of chronic wounds are recurrent bacterial infections, decreased angiogenesis, impaired tissue epithelialization and overabundance of ROS. The prolonged presence of neutrophils and M1 macrophages leads to a highly inflammatory profile in the wound. The process is enhanced by mast cells and CD8⁺ T cells’ activity. The level of other inflammatory T cell subtypes, such as Th1, Th17 and Th22, is also increased. Various MMPs, secreted by keratinocytes, contribute to defective re-epithelialization. Together, all those pathological processes promote inflammation, tissue fibrosis and poor vascularization.