The Role of IL-6 in Skin Fibrosis and Cutaneous Wound Healing

Abstract

The timely resolution of wound healing is critical for restoring the skin as a protective barrier. The switch from a proinflammatory to a reparative microenvironment must be tightly regulated. Interleukin (IL)-6 is a key modulator of the inflammatory and reparative process: it is involved in the differentiation, activation, and proliferation of leukocytes, endothelial cells, keratinocytes, and fibroblasts. This review examines the role of IL-6 in the healing of cutaneous wounds, and how dysregulation of IL-6 signaling can lead to either fibrosis or a failure to heal. The role of an IL-6/TGF-β feedback loop is discussed in the context of fibrogenesis, while IL-6 expression and responses in advanced age, diabetes, and obesity is outlined regarding the development of chronic wounds. Current research on therapies that modulate IL-6 is explored. Here, we consider IL-6's diverse impact on cutaneous wound healing.

Keywords: IL-6; fibrosis; skin; wounds.

Figure 1

The stages of wound healing. (a) The inflammatory phase begins with the influx of platelets and clotting factors which induce hemostasis to prevent blood loss. Inflammatory leukocytes enter the wound—neutrophils clear debris, while lymphocytes, monocytes and tissue-resident macrophages begin differentiating and releasing proinflammatory cytokines IL-1α, IL-1β, IL-6, IL-17, TNF-α, IFN-γ. This phase features predominately M1-type macrophages. (b) Proliferation begins with an influx of fibroblasts and TGF-β, resulting in the deposition of a collagen-I scaffold. M1 macrophages polarize towards an M2 phenotype which drives profibrotic signaling necessary for scaring. Keratinocytes migrate over the collagen scaffold and angiogenesis begins. (c) Remodeling occurs after a rigid collagen-rich scar has been established; over the course of months to years fibroblasts digest collagen-III and replace it with collagen-I while reorganizing the collagen fibers, which improves scar pliability. IL—interleukin; KGF—keratinocyte growth factor; MCP-1—monocyte chemoattractant protein 1; Th—T-helper; TGF-β—tissue growth factor β; VEGF—vascular endothelial growth factor.

Figure 2

IL-6 and TGF-β effects on leukocyte function. IL-6 promotes the proinflammatory functions of Th17, γδ T-cells, and M1 macrophages, while simultaneously promoting anti-inflammatory Th2 differentiation and cytokine secretion. IL-6 also stimulates profibrotic responses in M2 macrophages, in conjunction with M1/M2 polarization sustained by Th2 cytokines IL-4 and IL-23. TGF-β contributes to IL-6-dependent differentiation of Th17 and γδ T-cells. IL—interleukin; TGF-β—tissue growth factor β; Th—T-helper; TNF-α—tumor necrosis factor α; VEGF—vascular endothelial growth factor.

Figure 3

IL-6 and TGF-β-mediated interactions between dermal cells. IL-6 is central to profibrotic interactions between fibroblasts, myofibroblasts, keratinocytes and endothelial cells. IL-6 drives proliferation in endothelial cells in conjunction with VEGF, leading to neovascularization, which sustains pathological fibroproliferative scarring. IL-1β, TNF-α and IL-6 are produced by M1 macrophages in the wound site, while IL-17 is produced by Th17 and γδT-cells. Col-I—collagen 1; DD—Dupuytren’s disease IL—interleukin; KGF—keratinocyte growth factor; MCP-1—monocyte chemoattractant protein; MMP—matrix metalloproteinases; OSM—oncostatin M; SSc—systemic sclerosis; TGF-β—tissue growth factor β; TNF-α—tumor necrosis factor alpha; VEGF—vascular endothelial growth factor.