The use of tissue‐engineered skin to demonstrate the negative effect of CXCL5 on epidermal ultraviolet radiation‐induced cyclobutane pyrimidine dimer repair efficiency

Summary Background Ultraviolet radiation (UVR) is responsible for keratinocyte cancers through the induction of mutagenic cyclobutane pyrimidine dimers (CPDs). Many factors influence CPD repair in epidermal keratinocytes, and a better understanding of those factors might lead to prevention strategies against skin cancer. Objectives To evaluate the impact of dermal components on epidermal CPD repair efficiency and to investigate potential factors responsible for the dermal–epidermal crosstalk modulating UVR‐induced DNA damage repair in keratinocytes. Methods A model of self‐assembled tissue‐engineered skin containing human primary keratinocytes and fibroblasts was used in this study. Results We showed that CPD repair in keratinocytes is positively influenced by the presence of a dermis. We investigated the secretome and found that the cytokine CXCL5 is virtually absent from the culture medium of reconstructed skin, compared with media from fibroblasts and keratinocytes alone. By modulating CXCL5 levels in culture media of keratinocytes, we have shown that CXCL5 is an inhibitor of CPD repair. Conclusions This work outlines the impact of the secreted dermal components on epidermal UVR‐induced DNA damage repair and sheds light on a novel role of CXCL5 in CPD repair. What is already known about this topic? Repair of ultraviolet (UV)‐induced DNA damage is important in the prevention of skin cancer. The three‐dimensional environment of the skin promotes efficient epidermal repair of cyclobutane pyrimidine dimers. What does this study add? Using tissue‐engineered skin models, we show that the dermis positively influences UV‐induced DNA repair in the epidermis. Secreted molecules rather than extracellular components of the dermis influence DNA repair in the epidermis. CXCL5 is an inhibitor of UV‐induced DNA repair in keratinocytes What is the translational message? Ultraviolet radiation causes mutagenic damage to epidermal cells, which, if not repaired efficiently, can lead to skin cancers. We have shown that the dermis–epidermis interaction leads to a strong reduction of CXCL5, a repair inhibitor, which increases repair efficiency in the epidermis. By its action on CXCL5, the dermis increases repair efficiency of mutagenic damage in the epidermis and would thus have a protective effect against ultraviolet‐induced skin cancer. Linked Comment: Cadet. Br J Dermatol 2021; 184:9–10.