Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

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 and Kensuke Miyake ()
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Atsuo Kanno: The Institute of Medical Science, The University of Tokyo
Natsuko Tanimura: The Institute of Medical Science, The University of Tokyo
Masayuki Ishizaki: Daiichi Sankyo Shinagawa R&D center, Daiichi Sankyo Co. Ltd.
Kentaro Ohko: Kochi Medical School, Kochi University, Kohasu
Yuji Motoi: The Institute of Medical Science, The University of Tokyo
Masahiro Onji: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Ryutaro Fukui: The Institute of Medical Science, The University of Tokyo
Takaichi Shimozato: Daiichi Sankyo Shinagawa R&D center, Daiichi Sankyo Co. Ltd.
Kazuhide Yamamoto: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Takuma Shibata: The Institute of Medical Science, The University of Tokyo
Shigetoshi Sano: Kochi Medical School, Kochi University, Kohasu
Akiko Sugahara-Tobinai: Institute of Development, Aging and Cancer, Tohoku University
Toshiyuki Takai: Institute of Development, Aging and Cancer, Tohoku University
Umeharu Ohto: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
Toshiyuki Shimizu: CREST, Japan Science and Technology Agency
Shin-ichiroh Saitoh: The Institute of Medical Science, The University of Tokyo
Kensuke Miyake: The Institute of Medical Science, The University of Tokyo

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7119

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