Fig. 1.

The pathogenesis of UVR-induced photoaging in the skin. UVR exposure induces damages in DNA and ECM of the skin. UVR also enhances the generation of ROS/RNS compounds and thus it promotes oxidative stress. UVR-induced alterations elicit inflammatory state in the skin. Subsequently, inflammation stimulates the expansion of immunosuppressive cells in the skin, thus counteracting the inflammatory state. The expansion of Tregs, MDSCs, Bregs, and DCregs enhances immunosuppressive activity in the skin. There are several mechanisms which can evoke the immunosuppressive state in the skin: (i) UVR stimulates the generation of FICZ and cis-UCA compounds, (ii) inflammation stimulates the synthesis of KYN and KYNA, (iii) inflammation activates COX-2 and increases the generation of PGE2, (iv) immunosuppressive cells secrete anti-inflammatory cytokines, such as IL-10 and TGF-β, and (v) immune cells secrete amphiregulin which exerts a suppressive activity on Tregs. The activation of UVR-inflammation-immunosuppression pathway promotes the senescence of immune and non-immune cells in the skin. Senescent cells express a pro-inflammatory secretory phenotype (SASP) which is driving the pathological alterations evident in the skin. Chronic inflammation and the counteracting immunosuppression cause degenerative alterations in the skin inducing the photoaging state. Breg regulatory B cell, COX-2 cyclo-oxygenase-2, DCreg regulatory dendritic cell, ECM extracellular matrix, FICZ 6-formylindolo[3,2-b]carbazole, IL-10 interleukin-10, KYN kynurenine, KYNA kynurenic acid, MDSC myeloid-derived suppressor cell, PGE2 prostaglandin E2, SASP senescence-associated secretory phenotype, TGF-β transforming growth factor-β, Treg, regulatory T cell, UCA urocanic acid, UVR ultraviolet radiation