ニシオ　ジュンコ   Nishio Junko   西尾　純子    所属   東邦大学  医学部 医学科    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis.
掲載誌名	正式名：Proceedings of the National Academy of Sciences of the United States of America
掲載区分	国外
巻・号・頁	116(47),pp.23653-23661
著者・共著者	Hideo Negishi,Nobuyasu Endo,Yuki Nakajima,Tatsuaki Nishiyama,Yuichiro Tabunoki,Junko Nishio,Ryuji Koshiba,Atsushi Matsuda,Kosuke Matsuki,Tomohisa Okamura,Takako Negishi-Koga,Takeshi Ichinohe,Shunji Takemura,Hiroyuki Ishiwata,Shun-Ichiro Iemura,Tohru Natsume,Takaya Abe,Hiroshi Kiyonari,Takeshi Doi,Sho Hangai,Hideyuki Yanai,Keishi Fujio,Kazuhiko Yamamoto,Tadatsugu Taniguchi
発行年月	2019/11/19
概要	The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA's ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.
DOI	10.1073/pnas.1915326116
PMID	31694883