Abstract
High-mobility group box 1 (HMGB1) protein acts as a DNA chaperone for nuclear homeostasis. It translocates into the cytosol and is secreted into extracellular spaces, triggering proinflammatory cytokines and acting as a mediator in fibrosis. We determined whether HMGB1 plays a role in normal dermal fibrosis and keloid, and is involved with transforming growth factor β. We investigated the translocation and active release of HMGB1 from normal dermal fibroblasts under lipopolysaccharide stimuli, and the redistribution of nuclear HMGB1 into the cytoplasm of keloid fibroblasts. HMGB1 and its effector toll-like receptors and receptors for advanced glycation end product proteins are actively expressed in keloid tissues. Exogenous HMGB1 can induce the proliferation of human dermal fibroblasts, and could act as a profibrogenic molecule to produce collagen, decrease MMP-1, and increase TIMP-1 mRNA expression. Moreover, administration of HMGB1 increased the expression level of TGF-β1 and internal signaling molecules, such as Smad 2 and 3, phosphorylated Smad 2/3 complex, Erk 1/2, Akt, and NF-κB. Collectively, we demonstrate that HMGB1 treatment increases the expression level of collagen types I and III, elastin, and fibronectin in dermal spheroid cultures, thus making HMGB1 a promising therapeutic target for treatment of profibrogenic diseases.
Highlights
Keloid is a locally aggressive fibro-proliferative disorder of the skin
Evidence suggests that signaling by high-mobility group box 1 (HMGB1) or its receptors plays an essential role in mediating fibrotic diseases in the liver, kidneys, lung, and heart[13]
We hypothesized that HMGB1, a well-known initiator of inflammation, might be associated with normal dermal fibrosis and keloid, as is TGF-β
Summary
Keloid is a locally aggressive fibro-proliferative disorder of the skin. It is frequently accompanied by discomfort, contracture, and disfigurement[1]. HMGB1 is a nuclear, non-histone DNA-binding protein that acts as a DNA chaperone for nuclear homeostasis[12,13]. During cellular stress, it is released into the cytosol, and can exit the cell during loss of membrane integrity or active secretion[13,14]. Extracellular HMGB1 interacts with several receptors and coordinates cellular responses of immune system activation, cell migration, cell growth, and tissue repair and regeneration. Downstream signaling mediated by HMGB1 interaction involves mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB), and facilitates cellular responses www.nature.com/scientificreports/. We investigated the role of HMGB1 in skin fibrosis and keloid scar formation and its underlying mechanism. Our experiments elucidate the functions of HMGB1 and its crucial role in abnormal scarring process, and may lead to the acceptance of HMGB1 as a promising target for fibrotic disease therapy
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