The DNA Sugar Backbone 2′ Deoxyribose Determines Toll-like Receptor 9 Activation

Haas, Tobias; Metzger, Jochen; Schmitz, Frank; Heit, Antje; Müller, Thomas; Latz, Eicke; Wagner, Hermann

doi:10.1016/j.immuni.2008.01.013

Cited by 259 publications

(272 citation statements)

References 39 publications

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“…Unmethylated CpG dinucleotide motifs (Hartmann et al, 2000;Hemmi et al, 2000) promote activation of TLR9, and such a CpG sequence preference has also been reported for DNA binding to RAGE (Ruan et al, 2010). However, this sequence preference appears to be restricted to the nonnative form of phosphorothioate backbone, and TLR9 responses to the native phosphodiester DNA are sequence-independent (Haas et al, 2008). In agreement, our data strongly suggest that the DNA-RAGE interaction occurs irrespective of nucleotide sequence, and that RAGE serves to sample any type of "naked" extracellular nucleic acid.…”

Section: Protein Expression and Purification For Alphascreen Binding supporting

confidence: 81%

RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

Sirois¹,

Jin²,

Miller³

et al. 2014

Journal of Experimental Medicine

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Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE-DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.

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Section: Protein Expression and Purification For Alphascreen Binding supporting

confidence: 81%

RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

Sirois¹,

Jin²,

Miller³

et al. 2014

Journal of Experimental Medicine

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“…www.eji-journal.eu containing oligos that lack CpG motifs [21]. Interestingly, our data show that both ss and ds phosphodiester-containing ISD oligos can activate the IFN pathway, while phosphorothioate ISD oligos are inactive and can be used to block signaling.…”

Section: Discussionmentioning

confidence: 64%

“…The latter is reminiscent of TLR9-mediated recognition of DNA: TLR9 binds to and gets activated by the phosphodiester backbone and this response can be antagonized by phosphorothioate- containing oligos that lack CpG motifs [21]. Interestingly, our data show that both ss and ds phosphodiester-containing ISD oligos can activate the IFN pathway, while phosphorothioate ISD oligos are inactive and can be used to block signaling.…”

Section: Discussionmentioning

confidence: 73%

The TLR‐independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature

et al. 2009

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Recognition of foreign DNA by cytosolic innate immune receptors triggers the production of IFN-b. However, it is unclear whether different types of DNA ligands are recognized by similar receptors and whether the resulting response is distinct from the endosomal TLR response. To address these questions, we compared the two most commonly used types of DNA ligands (IFN-stimulatory DNA (ISD) and poly(dAdT)) and assessed the minimal structural requirements for stimulatory capacity in RAW264.7 cells. Gene expression signatures and competition experiments suggest that ISD and poly(dAdT) are qualitatively indistinguishable and differ from the CpG-containing oligonucleotides triggering the TLR9 pathway. Structure -activity relationship analyses revealed that a minimal length of two helical turns is sufficient for ISD-mediated IFN-b induction, while phosphorylation at the 5 0 -end is dispensable. Altogether, our data suggest that, in murine macrophages, only one major cytosolic DNA recognition pathway is operational. IntroductionInnate immunity represents the first line of defense against invading pathogens. PRR recognize molecular features that are conserved among many pathogens, so called PAMP. PRR are localized on the plasma membrane, the endosome or the cytosol and belong to distinct classes, most notably the TLR, the NOD-like receptors and the RIG-I-like helicases (RLH) [1,2]. Engagement of PRR by specific ligands triggers intracellular signaling cascades that culminate in the production and secretion of type-I IFN, cytokines and chemokines.An invading virus can either be sensed by endosomal TLR (TLR3, 7/8 or 9) or by cytosolic RLH [3], whereas, TLR3 and TLR7/8 recognize viral RNA, TLR9 senses the presence of viral DNA containing CpG motifs [4]. The RLH detect viral RNA in the cytosol [5]. This raises the question of how the host cell Eur. J. Immunol. 2009. 39: 1929-1936 DOI 10.1002 Innate immunity 1929distinguishes between viral and cellular RNA that are simultaneously present in the same subcellular compartment. It has recently been shown that many viral RNA, unlike cellular RNA, contain a triphosphate moiety at the 5 0 -end, which is recognized by RIG-I, the founding member of the RLH family [6,7]. Despite ''thousands of man-years worth of DNA transfections'', it has only recently been noticed that introduction of dsDNA into the cytosol triggers a potent innate immune response, leading to the production of IL-1b, IFN-b and other cytokines [8][9][10]. IL-1b secretion is governed by the DNA sensor AIM2 that has recently been identified [11][12][13][14]. IFN-b production is regulated by the DNA-dependent activator of IFN-regulatory factors (DAI, formerly known as DLM-1/ZBP1) [15] and as-yet unknown DNA sensors [16,17]. With regard to the IFN pathway, it has been suggested that the B-conformation of DNA is stimulatory, whereas Z-DNA is not [9]. Another report suggests that the exchange of the phosphate backbone for a phosphorothioate backbone renders the DNA inert, implying that the DNA backbone is the site of recog...

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“…Cytoplasmic expression may also be a method to avoid overstimulation gaining more specificity as suggested for other TLR. (28). Increase of cytoplasmic TLR 2 and TLR4 expression after stimulation with TLR ligands results in lower reactivity (29).…”

Section: Resultsmentioning

confidence: 99%

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Panzer

Blobel

Fölster‐Holst

et al. 2014

Experimental Dermatology

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The aim of the study was to investigate the expression of Toll-like receptors (TLRs) 2 and 4 on keratinocytes in atopic dermatitis, contact dermatitis, and psoriasis by PCR and by immunohistochemistry including confocal microscopy. Confocal microscopy revealed a granular intra-cellular expression pattern for TLR 2 and a homogenous intra-cellular expression pattern for TLR 4 in normal and diseased skin. TLR 2 was constitutively expressed in the suprabasal layers in normal skin, but limited to the basal epidermis in diseased skin. TLR 4 expression was concentrated to the basal layers in normal skin, whereas it was pronounced in upper layers in diseased skin. The shift in the TLR expression may be related to the disturbed skin barrier and a need for enhanced immune surveillance because of invading microbes. Also, there must be a balance between sufficient immune response and overstimulation.Abbreviation: TLR, Toll-like receptor.

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The DNA Sugar Backbone 2′ Deoxyribose Determines Toll-like Receptor 9 Activation

Cited by 259 publications

References 39 publications

RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

The TLR‐independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

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