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
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.