Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases.

Atsuo Kanno,Natsuko Tanimura,Shigetoshi Sano,Takuma Shibata,Kazuhide Yamamoto,Ryutaro Fukui,Umeharu Ohto,Takaichi Shimozato,Toshiyuki Shimizu,Kensuke Miyake,Toshiyuki Takai,Masahiro Onji,Kentaro Ohko,Shin-Ichiroh Saitoh,Yuji Motoi,Masayuki Ishizaki,Akiko Sugahara-Tobinai

doi:10.1038/ncomms7119

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 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.

Highlights

Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can potentially respond to self-derived RNA
A recently characterized anti-mouse TLR7 monoclonal Ab20 was used to reveal cell surface TLR7 on bone marrow-derived macrophages (BM-MCs; Fig. 1a)
The present study shows that TLR7 can be targeted by

Summary

Introduction

Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can potentially respond to self-derived RNA. 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. 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. Toll-like receptors 7 (TLR7) and 9 (TLR9), which act as innate immune sensors of microbial NAs3, erroneously respond to self-NAs, inducing antinuclear autoantibody production in murine models of systemic lupus erythematosus (SLE)[4,5,6]. The trafficking of TLR7 and TLR9 out of the endoplasmic reticulum (ER) is dependent on Unc93B1, a multiple transmembrane protein associated with TLR7 or TLR9 (refs 12,13)

Methods

Results

Conclusion