TY - JOUR
T1 - Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases
AU - Kanno, Atsuo
AU - Tanimura, Natsuko
AU - Ishizaki, Masayuki
AU - Ohko, Kentaro
AU - Motoi, Yuji
AU - Onji, Masahiro
AU - Fukui, Ryutaro
AU - Shimozato, Takaichi
AU - Yamamoto, Kazuhide
AU - Shibata, Takuma
AU - Sano, Shigetoshi
AU - Sugahara-Tobinai, Akiko
AU - Takai, Toshiyuki
AU - Ohto, Umeharu
AU - Shimizu, Toshiyuki
AU - Saitoh, Shin Ichiroh
AU - Miyake, Kensuke
N1 - Funding Information:
Supplementary Information accompanies this paper at http://www.nature.com/ naturecommunications Competing financial interests: M.I. and T.Sm. are employees of Daiichi-Sankyo Co. Ltd. K.M. is supported in part by a collaborative research grant from Daiichi-Sankyo Co. Ltd. The remaining authors declare no competing financial interests.
Funding Information:
We thank Professors Shizuo Akira (Osaka University) and Bruce Beutler (University of Texas) for providing mouse strains. This work was supported in part by a contract research fund from the Ministry of Education, Culture, Sports, Science and Technology for the Program of Japan Initiative for Global Research Network on Infectious Diseases, a Grant-in-Aid for Scientific Research on Innovative Areas, a Grant-in-Aid for Scientific Research (A), CREST, a collaborative research grant from Daiichi-Sankyo Co. Ltd. and the Translational Research Network Program.
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/2/4
Y1 - 2015/2/4
N2 - 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 Unc93b1 D34A/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.
AB - 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 Unc93b1 D34A/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.
UR - http://www.scopus.com/inward/record.url?scp=84929640671&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929640671&partnerID=8YFLogxK
U2 - 10.1038/ncomms7119
DO - 10.1038/ncomms7119
M3 - Article
AN - SCOPUS:84929640671
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 6119
ER -
