Abstract
Epidermal photoaging contributes to skin fragility over time and it is a risk factor for skin cancer. Photoaging has been associated for a long time with exposure to Ultraviolet-A (UVA) light, the predominant component of the solar ultraviolet radiation. While the cellular mechanisms underlying UVA-induced photoaging in the dermis have been well characterized, UVA’s action on the epidermis remains elusive. Here, proteomic analysis was conducted to derive the cellular responses induced by an environmentally relevant dose of UVA in primary human keratinocytes. We also investigated the effects of UVA on non-transformed immortalized keratinocytes (HaCaT cells), bearing potentially oncogenic mutations. We showed that UVA induces proteome remodeling and senescence in primary keratinocytes, eliciting potent antioxidant and pro-inflammatory responses. Additionally, we showed that UVA modulates the secretory phenotype of these cells to the extent of inducing paracrine oxidative stress and immune system activation in pre-malignant keratinocytes. These observations offer insights into the cellular mechanisms by which UVA drives photoaging in the skin.
Highlights
The solar ultraviolet radiation that reaches the Earth comprises about 5% of UVB (290–320 nm) and 95% of UVA light (320–400 nm), and both are strongly associated with skin photoaging and tumorigenesis[1]
We first tested if exposure to an environmentally relevant and non-cytotoxic low dose of UVA light could promote changes in protein levels of normal human epidermal keratinocytes (NHEK cells)
The up-regulated cluster is associated to immune system activation, detoxification of reactive species, and increased levels of structural mitochondrial proteins (Fig. 5C). These results suggest that exposure of immortalized HaCaT cells to senescent primary keratinocytes elicits a continuous anti-oxidant and pro-inflammatory response in these cells
Summary
The solar ultraviolet radiation that reaches the Earth comprises about 5% of UVB (290–320 nm) and 95% of UVA light (320–400 nm), and both are strongly associated with skin photoaging and tumorigenesis[1]. While the mechanisms underlying UVB carcinogenicity have been well-described for at least 60 years[2], involving direct generation of bipyrimidine photoproducts, UVA has only been classified as “probably carcinogenic to humans” by the World Health Organization’s International Agency for Research on Cancer in 2 0091 and many of its cellular effects remain unknown This is due to the fact that UVA is poorly absorbed by canonical nucleotides, causing much less direct DNA damage than U VB3. Dermal changes during aging reflect senescence as well as death of fibroblasts, which are constantly remodeling the connective tissue by secretion of soluble factors and extracellular matrix repertoire, both under homeostasis and cellular stress conditions[6] In this sense, UVA have been shown to induce alterations in the gene expression signatures of fibroblasts, modulating their secretory capacity, and eventually leading to apoptosis and senescence[5,7]. Mutations and dysfunctional components of the senescence machinery, providing a proteomic characterization of the differential sensitivity of the two cell types to the radiation
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