Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing

Fukui, Ryutaro; Saitoh, Shu‐ichi; Matsumoto, Fumi; Kozuka‐Hata, Hiroko; Oyama, Masaaki; Tabeta, Koichi; Beutler, Bruce; Miyake, Kensuke

doi:10.1084/jem.20082316

Cited by 168 publications

(165 citation statements)

References 52 publications

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“…1b). Unc93B1, a multiple transmembrane protein, associates with TLR7 or 9 and transports them from the ER to endolysosomes 13,15,21 . Our recent study shows that TLR9 is expressed on the surface of splenic DCs in a Unc93B1-dependent manner 21 .…”

Section: Resultsmentioning

confidence: 99%

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

et al. 2015

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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.

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Section: Resultsmentioning

confidence: 99%

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

et al. 2015

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“…IL-3 was added to the culture medium for the Ba/F3 cells. The construction of a Ba/F3 line with NF-kB-GFP (BakB) was described previously 21 .…”

Section: Methodsmentioning

confidence: 99%

“…BM-cDCs and BM-pDCs were prepared as described previously 21 . Briefly, BM cells were flushed from mouse tibiae and femurs.…”

Section: Methodsmentioning

confidence: 99%

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An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

et al. 2013

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Toll-like receptor 9 (TLR9) is an innate immune sensor for microbial DNA that erroneously responds to self DNA in autoimmune disease. To prevent autoimmune responses, Toll-like receptor 9 is excluded from the cell surface and silenced until the N-terminal half of the ectodomain (TLR9N) is cleaved off in the endolysosome. Truncated Toll-like receptor 9 (TLR9C) senses ingested microbial DNA, although the precise role of the truncation remains controversial. Here we show that TLR9 is expressed on the surface of splenic dendritic cells. Following the cleavage of TLR9 in the endolysosome, N-terminal half of the ectodomain remains associated with truncated TLR9, forming the complex TLR9N þ C. The TLR9-dependent cytokine production by Tlr9 À / À dendritic cells is rescued by a combination of TLR9N and TLR9C, but not by TLR9C alone. These results demonstrate that the TLR9N þ C complex is a bona fide DNA sensor.

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“…To avoid unnecessary stimulation of TLR7/9, they reside in the ER at the quiescent stage and traffic to endosomes only upon ligand recognition. Recently, Unc93B1, a multitransmembrane ERresident protein has been shown to associate with and deliver TLR7/9 from the ER to endosomes, where TLR7/9 recognizes their ligands [40]. In addition, gp96, an ER-resident HSP, has been shown to be a master immune chaperone for both cell surface and intracellular TLRs, including TLR1,2,4,5,7, and 9 [26].…”

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Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

et al. 2015

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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.Keywords: Hsp90 r IFN-α r Plasmacytoid DC r SLE r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSystemic lupus erythematosus (SLE) is characterized by the generation of autoantibodies specific for native double-stranded (ds) Correspondence: Prof. Yasuaki Tamura e-mail: ytamura3566@gmail.com DNA and nucleic acid/protein complexes [1]. A growing body of evidence suggests that IFN-α promotes lupus [2], since many patients have elevated serum IFN-α levels [3,4] and PBMCs from patients exhibit an IFN-α-induced gene expression signature that correlates with disease severity [5,6]. Recent findings in both human and mouse models suggest that TLR7 and TLR9 may play central roles in maintenance and progression of the disease by C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 2028-2041 Innate immunity 2029 promoting elevation of IFN-α levels from plasmacytoid dendritic cells (pDCs) [7][8][9] and by activating B cells to produce autoantibodies [10,11]. pDCs sense microbial nucleic acids by TLR7 and TLR9 and produce a large amount of IFN-α. pDCs specifically express TLR7 and TLR9 within endolysosmes, and TLR7 and TLR9 sense single-stranded RNA and unmethylated CpG-rich DNA [12][13][14][15]. Importantly, microbial nucleic acids share a basic structure with host-derived nucleic acids. Indeed, TLR9 is able to respond to mammalian DNA if expressed on the cell surface [16]. TLR7 also responds to host-derived single-stranded RNA [7]. Therefore, nucleic acid-sensing TLR7/9 has to be tightly controlled to avoid autoimmune reaction. Nucleic acid sensing within endolysosomes is thought to be a safety mechanism for self-nucleic acid, because self-nucleic acids are rapidly degraded by DNase and RNase before reaching endolysosomes. Self-derived nuc...

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Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing

Cited by 168 publications

References 52 publications

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

Heat shock protein 90 associates with Toll‐like receptors 7/9 and mediates self‐nucleic acid recognition in SLE

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