Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8

Ganguly, Dipyaman; Chamilos, Georgios; Lande, Roberto; Gregorio, Josh; Meller, Stephan; Facchinetti, Valeria; Homey, Bernhard; Barrat, Franck J.; Żal, Tomasz; Gilliet, Michel

doi:10.1084/jem.20090480

Cited by 617 publications

(614 citation statements)

References 44 publications

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“…The inhibitory effect of the anti-TLR7 mAb ameliorated a variety of inflammatory symptoms observed in Unc93b1 D34A/D34A mice. TLR7 has been implicated in a variety of autoimmune diseases 6,31 . By using inhibitory oligodeoxynucleotides, TLR7 has been shown to be a promising target for therapeutic intervention in mouse models of psoriasis and SLE 18,19 .…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

et al. 2015

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“…In psoriasis, a recently reported mechanism of PDCs activation is based on the production of the endogenous antimicrobial peptide LL37 by damaged keratinocytes. LL37 is able to bind and convert self-DNA or self-RNA into potent TLR-dependent PDCs triggers [64,65]. Remarkably, LL37 is induced strongly in the lesional epidermis of psoriasis biopsies [66].…”

Section: Box 1 the Chemerin/chemr23 Axis In Inflammationmentioning

confidence: 99%

Trafficking properties of plasmacytoid dendritic cells in health and disease

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et al. 2010

Trends in Immunology

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“…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 nucleic acids, however, may reach endolysosomes in an inflammatory or autoimmune situation, where a variety of nucleic acid-binding proteins such as autoantibodies, anti-microbial peptide LL-37 [17], and a nuclear protein, high-mobility group box 1 protein [18], are complexed with host nucleic acids. We have recently demonstrated that host DNA complexed with Hsp90 stimulated TLR9 signaling, leading to robust IFN-α production [19].…”

Section: Introductionmentioning

confidence: 99%

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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Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8

Cited by 617 publications

References 44 publications

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases

Trafficking properties of plasmacytoid dendritic cells in health and disease

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

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