title: Nuclear DNA damage-triggered NLRP3 inflammasome activation promotes UVB-induced inflammatory responses in human keratinocytes.
abstract: Ultraviolet (UV) radiation in sunlight can result in DNA damage and an inflammatory reaction of the skin commonly known as sunburn, which in turn can lead to cutaneous tissue disorders. However, little has been known about how UV-induced DNA damage mediates the release of inflammatory mediators from keratinocytes. Here, we show that UVB radiation intensity-dependently increases NLRP3 gene expression and IL-1β production in human keratinocytes. Knockdown of NLRP3 with siRNA suppresses UVB-induced production of not only IL-1β, but also other inflammatory mediators, including IL-1α, IL-6, TNF-α, and PGE2. In addition, inhibition of DNA damage repair by knockdown of XPA, which is a major component of the nucleotide excision repair system, causes accumulation of cyclobutane pyrimidine dimer (CPD) and activation of NLRP3 inflammasome. In vivo immunofluorescence analysis confirmed that NLRP3 expression is also elevated in UV-irradiated human epidermis. Overall, our findings indicate that UVB-induced DNA damage initiates NLRP3 inflammasome activation, leading to release of various inflammatory mediators from human keratinocytes.
authors.affiliation: Shiseido Life Science Research Center, 2-2-1, Hayabuchi, Tsuzuki-ku, Yokohama 224-8558, Japan. Electronic address: tatsuya.hasegawa@to.shiseido.co.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Shiseido Life Science Research Center, 2-2-1, Hayabuchi, Tsuzuki-ku, Yokohama 224-8558, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Shiseido Life Science Research Center, 2-2-1, Hayabuchi, Tsuzuki-ku, Yokohama 224-8558, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D002467:Cell Nucleus / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology*; D015603:Keratinocytes / Q000473:pathology / Q000528:radiation effects*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human