6-Formylindolo[3,2-b]Carbazole Accelerates Skin Wound Healing via Activation of ERK, but Not Aryl Hydrocarbon Receptor

Abstract

Wound healing is an elaborate process composed of overlapping phases, such as proliferation and remodeling, and is delayed in several circumstances, including diabetes. Although several treatment strategies for chronic wounds, such as growth factors, have been applied, further alternatives are required. The skin, especially keratinocytes, is continually exposed to UV rays, which impairs wound healing. 6-Formylindolo[3,2-b]carbazole (FICZ) is a tryptophan photoproduct formed by UV exposure, indicating that FICZ might be one of the effectors of UV radiation. In contrast, treatment with tryptophan, the precursor for FICZ, promoted wound closure in keratinocytes. Therefore, the aim of our study was to determine the role of FICZ in wound healing. Here we showed that FICZ enhanced keratinocyte migration through mitogen-activated protein kinase/extracellular signal-regulated kinase activation, and promoted wound healing in various mouse models, including db/db mice, which exhibit wound healing impairments because of type 2 diabetes. Moreover, FICZ, the endogenous ligand of an aryl hydrocarbon receptor, accelerated migration even in the aryl hydrocarbon receptor knockdown condition and also promoted wound healing in DBA/2 mice, bearing a low-affinity aryl hydrocarbon receptor, suggesting that FICZ enhanced keratinocyte migration in a mitogen-activated protein kinase/extracellular signal-regulated kinase-dependent, but aryl hydrocarbon receptor-independent, manner. The function of FICZ might indicate the possibility of its clinical use for intractable chronic wounds.

Glyteer, Soybean Tar, Impairs IL-4/Stat6 Signaling in Murine Bone Marrow-Derived Dendritic Cells: The Basis of Its Therapeutic Effect on Atopic Dermatitis

“…Our recent study showed that FICZ interferes with TGF-β signaling in human fibroblasts in an Ahr-independent manner [ 29 ]. We have also reported that FICZ accelerates wound healing via ERK signaling but not via Ahr signaling in human keratinocytes [ 30 ]. These findings are consistent with another report describing that an endogenous aryl hydrocarbon Ahr ligand, 2-(1′ H -indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), impaired TGF-β signaling in an Ahr-independent manner [ 31 ], indicating that Ahr ligands including Glyteer, FICZ and ITE have the ability to activate not only the canonical Ahr signaling pathway but also the non-canonical Ahr signaling pathway.…”

Human Adipose-Derived Stem Cells Promote Seawater-Immersed Wound Healing by Activating Skin Stem Cells via the EGFR/MEK/ERK Pathway

“…Moreover, EGF secreted by ADSCs is the most important growth factor for skin reepithelialization. Previous studies have shown that the expression of EGF can activate the MEK/ERK signaling pathway and promote cell proliferation and migration [25]. We found that there was a prolonged block of EGF expression in skin wounds following SW immersion, which further hindered the activation of the MEK/ERK signaling pathway and delayed the reepithelialization of skin wounds, as shown in Figure 6(d).…”

“…The expression levels of EGF protein (Figures 6(a) and 6(b)) indicate that hADSCs promote the expression of EGFR in skin wounds. Further, previous studies have shown that EGFR can regulate the activity of the MEK/ERK pathway [25]. Therefore, we examined the activity of the MEK/ERK pathway in repairing wounds.…”

Possible Roles of Proinflammatory Signaling in Keratinocytes Through Aryl Hydrocarbon Receptor Ligands for the Development of Squamous Cell Carcinoma

“…Polycyclic aromatic hydrocarbons (PAHs) exert their biological effects via binding to the ligand-activated transcription factor AhR, which activates the expression of genes encoding detoxification enzymes ( 9 ). Chronic exposure of skin to PAHs, such as DMBA, induces chronic keratinocyte-specific activation of the AhR, which leads to the symptoms of atopic dermatitis with chronic inflammation ( 6 ).…”