Dissecting the Impact of α-MSH-MC1R-cAMP Signaling on UVA-Induced Stress in Fibroblasts - Implications for Regulation of Cutaneous Photoaging

Alpha-melanocyte-stimulating hormone (α-MSH) is a key endocrine mediator of photoprotection in the ultraviolet (UV)B-induced skin response. Its effects are mediated by the melanocortin-1 (MC1R) receptor and include increased eumelanin synthesis but also direct cytoprotective actions. Previous studies have shown that individuals with the red hair and fair skin phenotype, carrying loss-of-function MC1R alleles, exhibited accelerated dermal photoaging. The underlying mechanism remains poorly understood. Here, we investigated the impact of α-MSH-MC1R-cAMP signalling on UVA-induced stress in key cells of dermal photoaging. Primary human dermal fibroblasts from adult donors were genotyped for common MC1R variants and analysed in both 2D monolayer and 3D spheroid culture models. UVA-induced oxidative stress and induction of genes related to the DNA damage response and senescence-associated secretory phenotype were assessed by flow cytometric analysis, real-time PCR, Western immunoblotting and ELISA. Functional MC1R signalling was evaluated by cAMP assays, with receptor expression examined by RT-PCR and Western immunoblotting. UVA exposure induced oxidative stress, and upregulation of p21, heme oxygenase-1, Sirtuin 1, interleukin-6 and -8. Although MC1R expression and functional cAMP signalling were confirmed, α-MSH treatment did not attenuate these UVA-induced stress responses. In accordance with this, pharmacological activation of canonical cAMP signalling did not alter the examined UVA-induced oxidative stress and inflammatory cell responses. Our findings do not provide evidence for a direct UVA-photoprotective effect of the α-MSH-MC1R axis in adult dermal fibroblasts. However, they do not exclude that a functional α-MSH-MC1R-cAMP signalling axis in other cell types of the skin is important in preventing photoaging.