TLR4 epidermal genetic deletion protects against acute and tumorigenic UV exposure in SKH-1 mouse skin.

Epidermal keratinocytes play a key role in regulating skin immune responses. However, their specific involvement in inflammatory signaling triggered by solar ultraviolet (UV) radiation, which contributes to the development of cutaneous squamous cell carcinoma, is not yet fully understood. It is now known that environmental UV exposure activates Toll-Like Receptor 4 (TLR4), initiating inflammatory signaling pathways. Given the emerging evidence linking TLR4 to UV-induced skin damage, we recently tested the TLR4 antagonist resatorvid (TAK-242) in SKH-1 mouse models. Our findings show that topical application of resatorvid significantly reduces UV-induced inflammatory signaling and lowers the incidence of skin cancer in these models. We have now generated transgenic mice allowing comparison between Tlr4 knockout confined to epidermal keratinocytes versus total systemic knockout status to examine its role in the modulation of solar UV-induced responses. Using transcriptomic and proteomic analysis, together with immune profiling, we observed that epidermal Tlr4 knockout mice are protected against UV-induced acute photodamage and chronic UV-induced photocarcinogenesis. Strikingly, epidermal KO status mimics the photoprotective impact of pharmacological antagonism (topical resatorvid), an effect not observed in transgenic mice harboring systemic deletion of Tlr4. Taken together, these findings demonstrate that epidermal TLR4 represents a promising target for skin cancer photochemoprevention.