UV exposure modulates hemidesmosome plasticity, contributing to long‐term pigmentation in human skin

Abstract

Human skin color, i.e. pigmentation, differs widely among individuals as do their responses to various types of ultraviolet radiation (UV) and their risks of skin cancer. In some individuals UV-induced pigmentation persists for months to years in a phenomenon termed long-lasting pigmentation (LLP). It is unclear whether LLP is an indicator of potential risk for skin cancer. LLP seems to have similar features to other forms of hyperpigmentation, e.g. solar lentigines or age spots, which are clinical markers of photodamage and risk factors for precancerous lesions. To investigate what UV-induced molecular changes may persist in individuals with LLP, clinical specimens from non-sunburn-inducing repeated UV exposures (UVA, UVB or UVA+UVB) at 4 months post-exposure (short-term LLP) were evaluated by microarray analysis and dataset mining. Validated targets were further evaluated in clinical specimens from 6 healthy individuals (3 LLP+ and 3 LLP-) followed for more than 9 months (long-term LLP) who initially received a single sunburn-inducing UVA+UVB exposure. The results support a UV-induced hyperpigmentation model in which basal keratinocytes have an impaired ability to remove melanin that leads to a compensatory mechanism by neighboring keratinocytes with increased proliferative capacity to maintain skin homeostasis. The attenuated expression of SOX7 and other hemidesmosomal components (integrin α6β4 and plectin) leads to increased melanosome uptake by keratinocytes and points to a spatial regulation within the epidermis. The reduced density of hemidesmosomes provides supporting evidence for plasticity at the epidermal-dermal junction. Altered hemidesmosome plasticity, and the sustained nature of LLP, may be mediated by the role of SOX7 in basal keratinocytes. The long-term sustained subtle changes detected are modest, but sufficient to create dramatic visual differences in skin color. These results suggest that the hyperpigmentation phenomenon leading to increased interdigitation develops in order to maintain normal skin homeostasis in individuals with LLP.

Molecular and histological characterization of age spots

“…Therefore, we propose a model for how rete ridges develop and melanin pigment accumulates over time in age spots (shown schematically in Figure ). In age spots, early events in UV‐exposed skin might involve pigment‐related genes, as identified in previous studies, that initially increase melanocyte growth and differentiation, leading to increased skin pigmentation. Over time, in older subjects, the basal keratinocytes (KRT5‐positive) might proliferate more actively while suprabasal keratinocytes (KRT10‐positive) desquamate more slowly than in normal skin putting pressure on the basement membrane.…”

“…Interestingly, several other recent studies of hyperpigmented skin, the UV‐induced long‐lasting pigmentation LLP and ethnic skin, also showed that genes and mechanisms other than pigment‐related processes correlated with the increased pigmentation. A meta‐analysis study of five different models of hyperpigmented skin, including age spots, demonstrated that the expression of many genes that were not significantly different in any one of those studies, but did reach statistical significance when multiple studies were considered together (primarily due to the limited sample size in any individual study).…”

Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP‐10 and MET

“…SOX4 has also been implicated in lung epithelial cell‐mediated host defense against bacteria by regulating the expression of antimicrobial factors such as lysozyme . Furthermore, SOX7 is involved in basal keratinocyte function and in epidermal‐dermal junction plasticity and remodeling in the skin . Our data highlighted an inverse correlation between ETS1 and NKX3A, and MMP10 expression.…”

The promise of marine molecules as cosmetic active ingredients

“…) exhibit great tyrosinase inhibition as this region competes for DL‐DOPA inhibition , leading to decreased melanin production. This highlights a promising foundation of anti‐melanogenesis research, where several polyphenols and flavonoids are emerging as novel cosmetic and pharmaceutical ingredients, but mainly as antioxidants and photoprotectants .…”

“…2) exhibit great tyrosinase inhibition as this region competes for DL-DOPA inhibition [102], leading to decreased melanin production. This highlights a promising foundation of anti-melanogenesis research, where several polyphenols and flavonoids are emerging as novel cosmetic and pharmaceutical ingredients, but mainly as antioxidants and photoprotectants [83,84]. Fucoidan, also a phaeophyte secondary metabolite, has been documented as a potential anti-pigment treatment, with evidence for its mechanism of indirect melanogenesis inhibition [103,104], but has not yet been pursued as a cosmetic ingredient.…”