Pigment‐independent cAMP‐mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation

Abstract

The epidermis increases pigmentation and epidermal thickness in response to ultraviolet exposure to protect against UV-associated carcinogenesis; however, the contribution of epidermal thickness has been debated. In a humanized skin mouse model that maintains interfollicular epidermal melanocytes, we found that forskolin, a small molecule that directly activates adenylyl cyclase and promotes cAMP generation, up-regulated epidermal eumelanin accumulation in fair-skinned melanocortin-1-receptor (Mc1r)-defective animals. Forskolin-induced pigmentation was associated with a reproducible expansion of epidermal thickness irrespective of melanization or the presence of epidermal melanocytes. Rather, forskolin-enhanced epidermal thickening was mediated through increased keratinocyte proliferation, indirectly through secreted factor(s) from cutaneous fibroblasts. We identified keratinocyte growth factor (Kgf) as a forskolin-induced fibroblast-derived cytokine that promoted keratinocyte proliferation, as forskolin induced Kgf expression both in the skin and in primary fibroblasts. Lastly, we found that even in the absence of pigmentation, forskolin-induced epidermal thickening significantly diminished the amount of UVA and UVB that passed through whole skin and reduced the amount of UVB-associated epidermal sunburn cells. These findings suggest the possibility of pharmacologic-induced epidermal thickening as a novel UV-protective therapeutic intervention, particularly for individuals with defects in pigmentation and adaptive melanization.

The influence of exposome on acne

“…One of the major environmental factors affecting the skin is ultraviolet radiation (UVR). Both UVB and UVA have been reported to cause hyperplasia of the sebaceous gland, thickening of the stratum corneum , increase in sebum secretion and in the number of comedones . By targeting the cells and molecules within the skin, UVR triggers the production and release of antimicrobial peptides, activates the innate immune system and ultimately suppresses the adaptive cellular immune response.…”

UV Radiation and the Skin

“…Increased keratinocyte cell division after UV exposure leads to accumulation of epidermal keratinocytes which increases epidermal thickness. Epidermal hyperplasia protects the skin better against UV penetration [82]. …”

“…MC1R signaling also directly influences UV resistance of melanocytes by enhancing nucleotide excision DNA repair and oxidative resistance. Since MC1R signaling is potentially targetable by agents that influence cAMP levels [82,84,205], pharmacologic manipulation of cutaneous cAMP may be a useful approach to reduce UV sensitivity and cancer risk. Theoretically, raising cAMP levels in the skin can be accomplished either by stimulating its production (e.g., adenylyl cyclase activation) or by impeding its degradation (e.g., phosphodiesterase inhibition).…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…The local use of FSK for treatment of glaucoma is being explored, too (Majeed et al, 2015). Moreover, the dermatological application of FSK to protect the skin against ultraviolet light and induce persistent tanning is under investigation (Spry et al, 2009;Scott et al, 2012;Sikora et al, 2015). Furthermore, FSK derivatives are explored as anticancer compounds (Ponnam et al, 2014).…”