TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis

Abstract

Background: Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and inflammatory dysregulation is a key mechanism underlying detrimental effects of acute and chronic UV exposure. The health and economic burden of skin cancer treatment is substantial, creating an increasingly urgent need for the development of improved molecular strategies for photoprotection and photochemoprevention. Methods: A structured search of bibliographic databases for peer-reviewed research literature revealed 139 articles including our own that are presented and critically evaluated in this TLR4-directed review. Objective: To understand the molecular role of Toll-like receptor 4 (TLR4) as a key regulator of skin anti-microbial defense, wound healing, and cutaneous tumorigenic inflammation. The specific focus of this review is on recent published evidence suggesting that TLR4 represents a novel molecular target for skin photoprotection and cancer photochemoprevention. Results: Cumulative experimental evidence indicates that pharmacological and genetic antagonism of TLR4 suppresses UV-induced inflammatory signaling involving the attenuation of cutaneous NF-κB and AP-1 stress signaling observable in vitro and in vivo. TLR4-directed small molecule pharmacological antagonists [including eritoran, (+)-naloxone, ST2825, and resatorvid] have now been identified as a novel class of molecular therapeutics. TLR4 antagonists are in various stages of preclinical and clinical development for the modulation of dysregulated TLR4-dependent inflammatory signaling that may also contribute to skin photodamage and photocarcinogenesis in human populations. Conclusion: Future research should explore the skin photoprotective and photochemopreventive efficacy of topical TLR4 antagonism if employed in conjunction with other molecular strategies including sunscreens.