Hasegawa Tatsuya, Nakashima Masaya, Suzuki Yoshiharu
Shiseido Life Science Research Center, 2-2-1, Hayabuchi, Tsuzuki-ku, Yokohama 224-8558, Japan.
Shiseido Life Science Research Center, 2-2-1, Hayabuchi, Tsuzuki-ku, Yokohama 224-8558, Japan.
Biochem Biophys Res Commun. 2016 Aug 26;477(3):329-35. doi: 10.1016/j.bbrc.2016.06.106. Epub 2016 Jun 23.
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.
阳光中的紫外线（UV）辐射可导致DNA损伤以及皮肤的炎症反应，即通常所说的晒伤，进而可能引发皮肤组织紊乱。然而，关于紫外线诱导的DNA损伤如何介导角质形成细胞释放炎症介质，人们所知甚少。在此，我们发现紫外线B（UVB）辐射强度依赖性地增加人角质形成细胞中NLRP3基因的表达和白细胞介素-1β（IL-1β）的产生。用小干扰RNA（siRNA）敲低NLRP3不仅抑制UVB诱导的IL-1β产生，还抑制包括IL-1α、IL-6、肿瘤坏死因子-α（TNF-α）和前列腺素E2（PGE2）在内的其他炎症介质的产生。此外，通过敲低核苷酸切除修复系统的主要成分XPA来抑制DNA损伤修复，会导致环丁烷嘧啶二聚体（CPD）的积累和NLRP3炎性小体的激活。体内免疫荧光分析证实，在紫外线照射的人表皮中NLRP3表达也升高。总体而言，我们的研究结果表明，UVB诱导的DNA损伤引发NLRP3炎性小体激活，导致人角质形成细胞释放各种炎症介质。
