Exposure to ultraviolet radiation (UVR) damages skin cell DNA but skin cancers develop because UVR also affects the immune system. How does this occur? In 1983, De Fabo and Noonan identified a unique photoreceptor in skin — urocanic acid (UCA) — that is an important intermediary by which UV wavelengths of 250–320 nm lead to systemic immunosuppression. Importantly, the characteristics of UVR-induced skin tumour development matched those of UVR-mediated reduction in contact hypersensitivity (CHS) responses in mice with an intact epidermis. Furthermore, the dose–response relationship between UVR exposure and reduced CHS responses was very similar to the absorption spectrum of UCA, a major component of the epidermis, which isomerizes from the trans to the cis form upon irradiation.

UCA, a major component of the epidermis … isomerizes from the trans to the cis form upon irradiation

Once cis-UCA had been identified as a photoreceptor, research on its biochemical properties intensified. Many cells of the skin (keratinocytes, fibroblasts, dendritic cells, nerve cells and mast cells) and in the circulation (monocytes) can initiate signalling in response to cis-UCA, but its receptor in humans has been elusive; in mouse skin, it is the 5-HT2A receptor. Cis-UCA has been detected in serum and urine following UVR exposure, which may explain some of the systemic immunoregulatory effects induced by UVR. Recently, increased levels of UCA in the blood and brains of mice exposed to moderate levels of UVR were implicated in enhanced learning and memory (Zhu et al., 2018).

There are other UVR photoreceptors in skin, including 7-dehydrocholesterol, DNA, membrane phospholipids and tryptophan, but the in vivo action spectrum of UCA discovered by De Fabo and Noonan showed that these other candidate molecules are not the major UVR photoreceptors for inducing immunosuppression. Instead, they may have a co-operative role with trans-UCA, with their involvement determined by the UVR wavelengths to which the skin is exposed, the immune pathways under investigation and whether the experiments are carried out in humans or animal models. As UVR is such an important component of our environment, this is a rich area for research.