Saito Keita, Kukita Kazuharu, Kutomi Goro, Okuya Koichi, Asanuma Hiroko, Tabeya Tetsuya, Naishiro Yasuka, Yamamoto Motohisa, Takahashi Hiroki, Torigoe Toshihiko, Nakai Akira, Shinomura Yasuhisa, Hirata Koichi, Sato Noriyuki, Tamura Yasuaki
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Eur J Immunol. 2015 Jul;45(7):2028-41. doi: 10.1002/eji.201445293. Epub 2015 Apr 28.
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.
系统性红斑狼疮（SLE）是一种典型的系统性自身免疫性疾病，疾病活动度与血清干扰素-α（IFN-α）水平相关。浆细胞样树突状细胞（pDCs）通过Toll样受体7（TLR7）和9感知微生物及自身核酸，并产生大量IFN-α。在此，我们发现热休克蛋白90（Hsp90）与TLR7/9结合，并将其从内质网转运至早期内体进行配体识别。通过多种方法抑制Hsp90，包括使用Hsp90抑制剂（一种格尔德霉素衍生物），可抑制Hsp90与TLR7/9的结合，进而抑制IFN-α的产生，使小鼠的SLE症状得到改善。值得注意的是，我们观察到与非活动期疾病患者相比，活动期SLE患者血清Hsp90明显升高。此外，我们证明在SLE患者中检测到的血清Hsp90与自身DNA和/或抗DNA抗体结合，从而刺激pDCs产生IFN-α。我们的数据表明，Hsp90在SLE发病机制中起关键作用，因此Hsp90抑制剂将为SLE及其他核酸相关自身免疫性疾病提供一种新的治疗方法。
