Immunology of Wound Healing

Abstract

Purpose of review: Chronic wounds are a tremendous burden on the healthcare system and lead to significant patient morbidity and mortality. Normal cutaneous wound healing occurs through an intricate and delicate interplay between the immune system, keratinocytes, and dermal cells. Each cell type contributes signals that drive the normal phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This paper reviews how various immunological cell types and signaling molecules influence the way wounds develop, persist, and heal.

Recent findings: Concurrent with the achievement of hemostasis, neutrophils are the first cells to migrate to the wound bed, brought in by pro-inflammatory signals including IL-8. Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state, where angiogenesis occurs and granulation tissue is laid down. Myofibroblasts, activated through contractile forces and signaling molecules, then drive remodeling, where granulation tissue becomes scar. Unchecked inflammation at this stage can result in abnormal scar formation.

Summary: Although the derangement of immune signals at any stage can result in impaired wound healing, recent research has shown that the key transition point lies between the inflammatory and the proliferative phases. This review summarizes the events that facilitate this transition and discusses how this process can be disrupted, leading to chronic, non-healing wounds.

Keywords: Anti-inflammatory macrophage; Chronic wound; Macrophage; Neutrophil; Re-epithelialization; Wound healing.

Fig. 1

Legend: traditional model of wound healing. Wound healing normally progresses through the hemostasis/inflammatory phase, the proliferative phase, and the remodeling phase. Hemostasis is achieved with production of a fibrin clot. Danger signals are released from platelets and damaged cells, which leads to infiltration and activation of pro-inflammatory cells such as neutrophils and inflammatory-type macrophages. There is an important transition from the inflammatory to the proliferative phase (days 2–5). In chronic wounds, this transition often fails to occur. In the proliferative phase, extracellular matrix (ECM) is laid down to form granulation tissue, and angiogenesis and re-epithelialization occur. Over the next year, the granulation tissue is remodeled into a scar

Fig. 2

Legend: the transition from pro-inflammatory macrophages to anti-inflammatory macrophages is a key regulatory step, allowing the immune system to promote both ECM formation and re-epithelialization. During the inflammatory phase, pro-inflammatory macrophages dominate. They are activated by danger signals such as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) as well as pro-inflammatory cytokines. This phenotype is responsible for clearance of debris and prevention of infection. Persistence of inflammation results in a non-healing wound. Normally, macrophages transition to an anti-inflammatory phenotype in response to signals such as neutrophil apoptosis and engulfment (efferocytosis) as well as other local immune signals. This transition is inhibited in the setting of iron overload, hypoxia, and hyperglycemia. These pro-healing, anti-inflammatory macrophages are responsible for resolution of tissue inflammation and contribute to angiogenesis and tissue repair. During the proliferative phase, new blood vessels and granulation tissue are laid down and keratinocytes re-epithelialize. Pro-repair macrophages send signals to both fibroblasts and keratinocytes themselves. To keratinocytes, they release epidermal growth factor (EGF) and transforming growth factor-α (TGF-α), which drive keratinocyte proliferation and migration. Through platelet-derived growth factor (PDGF), TNF-α, IL-1, and IL-6, pro-repair macrophages signal fibroblasts to lay down granulation tissue, comprised of fibrin, fibronectin, as well as collagen. In turn, fibroblasts further stimulate keratinocyte proliferation and migration through keratinocyte growth factor (KGF), EGF, and fibronectin. Keratinocytes themselves also activate fibroblasts in a feedback loop through the production of fibronectin, tenascin C, and laminin 332