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Targeting cell surface ​TLR7 for therapeutic intervention in autoimmune diseases

Nature Communications 6, Article number: 6119 doi:10.1038/ncomms7119
Atsuo Kanno, Natsuko Tanimura, Masayuki Ishizaki, Kentaro Ohko, Yuji Motoi, Masahiro Onji, Ryutaro Fukui, Takaichi Shimozato, Kazuhide Yamamoto, Takuma Shibata, Shigetoshi Sano, Akiko Sugahara-Tobinai, Toshiyuki Takai, Umeharu Ohto, Toshiyuki Shimizu, Shin-ichiroh Saitoh & Kensuke Miyake
Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan Japan Society for the Promotion of Science, 5-3-1, Kojimachi, Chiyodaku, Tokyo 102 0083, Japan Daiichi Sankyo Shinagawa R&D center, Daiichi Sankyo Co. Ltd., 1-chome, Hiromachi, Tokyo 140 8710, Japan Department of Dermatology, Kochi Medical School, Kochi University, Kohasu, Okocho, Nankoku 783 8505, Japan Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700 8558, Japan CREST, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi-shi, Saitama 332 0012, Japan Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Sendai 980 8575, Japan Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113 0033, Japan

Toll-like receptor 7 (​TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, ​TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that ​TLR7 is present on the cell surface of immune cells and that ​TLR7 responses can be inhibited by an anti-​TLR7 antibody. The anti-​TLR7 antibody is internalized with ​TLR7 and accumulates in endolysosomes as an immune complex. ​TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-​TLR7 antibody. Furthermore, the anti-​TLR7 antibody inhibits in vivo cytokine production induced by a ​TLR7 ligand. Spontaneous ​TLR7 activation in ​Unc93b1D34A/D34A mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-​TLR7 antibody treatment. These results demonstrate that cell surface ​TLR7 is a promising target for therapeutic intervention in autoimmune diseases.