Crosstalk Among UV-Induced Inflammatory Mediators, DNA Damage and Epigenetic Regulators Facilitates Suppression of the Immune System

Abstract

The suppression of the immune system by overexposure to ultraviolet (UV) radiation has been implicated in the initiation and progression of photocarcinogenesis. Numerous changes occur in the skin on UVB exposure, including the generation of inflammatory mediators, DNA damage, epigenetic modifications, and migration and functional alterations in the antigen-presenting dendritic cells. Although each of these alterations can elicit a cascade of events that have the potential to modulate immune sensitivity alone, there is emerging evidence that there is considerable crosstalk between these cascades. The development of an understanding of UV-induced changes in the skin that culminate in UV-induced immunosuppression, which has been implicated in the risk of nonmelanoma skin cancer, as a network of events has implications for the development of more effective chemopreventive strategies. In the current review article, we discuss the evidence of interactions between the various molecular targets and signaling mechanisms associated with UV-induced immunosuppression.

Figure 1

Schematic diagram depicting dynamic crosstalk among UV radiation-induced inflammatory mediators, DNA damage, and epigenetic regulators in photo-immunosuppression. UVB induced photodamage initiates migration of antigen presenting cells from skin to regional lymph nodes, where they present antigen to T-cells in a way that is not normal due to photodamage of antigen presenting cells. UVB-induced inflammatory mediators and DNA damage affect epigenetic modifications (DNA hypermethylation) and together with infiltrating myeloid derived cells play crucial roles in suppression of immune system in UV radiation-exposed mice. UVR, ultraviolet radiation; CPDs, cyclobutane pyrimidine dimers; 6–4 PPs, 6–4 photoproducts; APCs, antigen presenting cells; PAF, Platelet activation factor; COX-2, cyclooxygenase-2; PGE₂, prostaglandin E₂; CD11b⁺ cells, activated macrophages and neutrophil cell population.