title: Heat shock protein 90 associates with Toll-like receptors 7/9 and mediates self-nucleic acid recognition in SLE.
abstract: Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease, and disease activity is associated with serum IFN-α level. Plasmacytoid dendritic cells (pDCs) sense microbial as well as self-nucleic acids by TLRs 7 and 9 and produce a large amount of IFN-α. Here, we show that heat shock protein 90 (Hsp90) associates with and delivers TLR7/9 from the ER to early endosomes for ligand recognition. Inhibition of Hsp90 by various approaches including the use of Hsp90 inhibitor, a geldanamycin derivative, suppressed the Hsp90 association with TLR7/9, which resulted in inhibition of IFN-α production, leading to improvement of SLE symptoms in mice. Notably, we observed that serum Hsp90 is clearly increased in patients with active SLE compared with that in patients with inactive disease. Furthermore, we demonstrated that serum Hsp90 detected in SLE patients binds to self-DNA and/or anti-DNA Ab, thus leading to stimulation of pDCs to produce IFN-α. Our data demonstrate that Hsp90 plays a crucial role in the pathogenesis of SLE and that an Hsp90 inhibitor will therefore provide a new therapeutic approach to SLE and other nucleic acid-related autoimmune diseases.
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Keita
authors: K
authors: Saito
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Kazuharu
authors: K
authors: Kukita
authors: Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Goro
authors: G
authors: Kutomi
authors: Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Koichi
authors: K
authors: Okuya
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Hiroko
authors: H
authors: Asanuma
authors: Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Tetsuya
authors: T
authors: Tabeya
authors: Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Yasuka
authors: Y
authors: Naishiro
authors: Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Motohisa
authors: M
authors: Yamamoto
authors: Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Hiroki
authors: H
authors: Takahashi
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Toshihiko
authors: T
authors: Torigoe
authors: Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Yamaguchi, Japan.
authors: Akira
authors: A
authors: Nakai
authors: Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Yasuhisa
authors: Y
authors: Shinomura
authors: Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Koichi
authors: K
authors: Hirata
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Noriyuki
authors: N
authors: Sato
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Molecular Therapeutics, Center for Food and Medical Innovation, Hokkaido University, Sapporo, Japan.
authors: Yasuaki
authors: Y
authors: Tamura
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D019463:Mice, Inbred MRL lpr; D018613:Microscopy, Confocal; D009696:Nucleic Acids / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens; D018841:HSP90 Heat-Shock Proteins; D016898:Interferon-alpha; D009696:Nucleic Acids; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9
keywords: Hsp90; IFN-α; Plasmacytoid DC; SLE; TLR