Skewing of UV-Induced Cell Death Pathways using TLR4 Ligands

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Abstract Ultraviolet (UV) radiation induces DNA damage resulting in epidermal cell mutations and immunosuppression contributing to the formation of nonmelanoma skin cancer. UV-induced cellular damage is commonly associated with apoptosis characterized by a non-inflammatory cell death through the cleavage and activation of caspase-3 which requires Toll-like receptor 4 (TLR4) signaling to activate the apoptotic signaling cascade. TLR4 is a cell associated innate immune receptor and has been shown to contribute to UV-induced carcinogenesis. We hypothesize that skewing cell death from apoptosis to necroptosis using lipid A mimetics to reduce TLR4 expression through tolerization can reduce apoptosis and lead to inflammatory cell death. Hexa-acylated and tetra-acylated lipid A memetics from Yersinia pestis (Y. pestis) are used to tolerize TLR4 in thioglycolate-induced macrophages (ThioMΦ). This will likely lead to the ThioMΦ cells being less susceptible to UV-induced carcinogenesis. To analyze the role of TLR4 in UV-induced carcinogenesis, cells that are TLR4-proficient, TLR4-deficient, and TLR4 tolerized with lipid A were exposed to multiple doses of UVB radiation. UV-irradiated ThioMΦ cells were surveyed for markers of DNA repair and cell death mechanism. Our data indicates that exposure to lipid A attenuates TLR4-mediated apoptotic cell death and, likely, downstream immune suppression. TLR4 ligands may be useful in prophylactic treatment approaches against UV-induced carcinogenesis.