An updated review of the immunological mechanisms of keloid scars

Abstract

Keloid is a type of disfiguring pathological scarring unique to human skin. The disorder is characterized by excessive collagen deposition. Immune cell infiltration is a hallmark of both normal and pathological tissue repair. However, the immunopathological mechanisms of keloid remain unclear. Recent studies have uncovered the pivotal role of both innate and adaptive immunity in modulating the aberrant behavior of keloid fibroblasts. Several novel therapeutics attempting to restore regulation of the immune microenvironment have shown variable efficacy. We review the current understanding of keloid immunopathogenesis and highlight the potential roles of immune pathway-specific therapeutics.

Keywords: T lymphocytes; cytokines; immunity; keloid; macrophages; scar; signal transduction.

Figure 1

The role of mast cells in keloid pathogenesis. Degranulated mast cells crosstalk with activated keloid fibroblasts via the PI3K/Akt/mTOR pathway, leading to more collagen synthesis. Enzymes, growth factors, and cytokines released upon mast cell degranulation contribute to activation of the RAS, upregulation of keloid fibroblasts, angiogenesis, and cutaneous symptoms. AT-II, angiotensin II; FGF-2, fibroblast growth factor 2; IL, interleukin; PDGF, platelet-derived growth factor; PI3K/Akt/mTOR, phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin pathway; RAS, renin–angiotensin system; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Figure 2

The role of macrophages in keloid pathogenesis. M2 macrophages predominate in keloids, resulting in activation of keloid fibroblasts, Treg differentiation, and fibrosis and angiogenesis. IGF-1, insulin-like growth factor 1; IL, interleukin; PDGF, platelet-derived growth factor; TGF-β1, transforming growth factor β1; Th, helper T cells; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.

Figure 3

The role of regulatory T cells in keloid pathogenesis. Tregs exert effects through the action of IL-10 and TGF-β1, leading to suppression of M1 macrophages, activation of keloid fibroblasts, and mast cell production of IL-6. IL, interleukin; TGF-β1, transforming growth factor β1; Tregs, regulatory T cells.

Figure 4

Signaling pathways involved in keloid formation. Several downstream pathways of TGF-β1 participate in keloid pathogenesis. Mechanical stimuli exert an effect through Rho/ROCK and YAP/TAZ, leading to the modulation of canonical TGF-β1 signaling. The interleukin family of cytokines and NEDD4 exert profibrotic action via STAT3, independent of TGF-β1. ERK, extracellular signal-regulated kinase; IL, interleukin; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; mTOR, mammalian target of rapamycin; NEDD4, neural precursor cell expressed, developmentally downregulated 4; PI3K, phosphatidylinositol-3-kinase; ROCK, RhoA/Rho-associated protein kinase; STAT3, signal transducer and activator of transcription 3; TGF-β1, transforming growth factor β1; TYK2, tyrosine kinase 2; YAP/TAZ, Yes-associated protein/transcriptional coactivator with PDZ-binding motif.