DNA Motifs Suppressing TLR9 Responses

Trieu, Angela; Roberts, Tara L.; Dunn, Jasmyn A.; Sweet, Matthew J.; Stacey, Katryn J.

doi:10.1615/critrevimmunol.v26.i6.50

Cited by 33 publications

(41 citation statements)

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“…Similarly, IFN-α production by human PBMCs in response to our DNA-IC were reduced in the presence of antagonistic ODN (Figure S1D) or chloroquine (Figure S1E), both of which inhibit TLR9 activation (Trieu et al, 2006; Macfarlane and Manzel, 1998). We further investigated our model of in vitro formed DNA-IC in fetal liver-derived murine pDCs, a cell type that in our knowledge has not previously been used to investigate TLR9 responses and that was used throughout the current study.…”

Section: Resultsmentioning

confidence: 82%

Noncanonical Autophagy Is Required for Type I Interferon Secretion in Response to DNA-Immune Complexes

Hénault¹,

Martinez

Riggs³

et al. 2012

Immunity

315

343

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SUMMARY Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment.

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Section: Resultsmentioning

confidence: 82%

Noncanonical Autophagy Is Required for Type I Interferon Secretion in Response to DNA-Immune Complexes

Hénault¹,

Martinez

Riggs³

et al. 2012

Immunity

315

343

View full text Add to dashboard Cite

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“…In keeping with A151’s effects on TLR9 activation conversion to a phosphodiester backbone (PD) completely abolished A151-mediated inhibition of IFI16 and AIM2 at the concentrations tested (41). Sequence also proved to be important; substitution of A151’s guanosine triplet with adenosine residues reduced construct potency by 94%.…”

Section: Discussionmentioning

confidence: 86%

Synthetic Oligodeoxynucleotides Containing Suppressive TTAGGG Motifs Inhibit AIM2 Inflammasome Activation

Kaminski

Schattgen

Tzeng

et al. 2013

The Journal of Immunology

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Synthetic oligodeoxynucleotides comprised of the immunosuppressive motif TTAGGG block TLR9 signaling, prevent STAT1 and STAT4 phosphorylation and attenuate a variety of inflammatory responses in vivo. Here, we demonstrate that such suppressive oligodeoxynucleotides (sup ODN) abrogate activation of cytosolic nucleic acid sensing pathways. Pretreatment of dendritic cells and macrophages with the suppressive ODN-A151 abrogated type I IFN, TNFα and ISG induction in response to cytosolic dsDNA. In addition, A151 abrogated caspase-1-dependent IL-1β and IL-18 maturation in dendritic cells stimulated with dsDNA and murine cytomegalovirus (MCMV). Inhibition was dependent on A151’s phosphorothioate backbone while substitution of the guanosine residues for adenosine negatively affected potency. A151 mediates these effects by binding to AIM2 in a manner that is competitive with immune-stimulatory DNA and as a consequence prevents AIM2 inflammasome complex formation. Collectively, these findings reveal a new route by which suppressive ODNs modulate the immune system and unveil novel applications for suppressive ODNs in the treatment of infectious and autoimmune diseases.

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“…To further confirm the participation of TLR7/9 in apoptotic MMP-mediated pDC activation, MMP stimulation was carried out in the presence of the G-rich inhibitory ODN (iODN) PZ3, which was previously shown to interfere with TLR9 activity (46,47). The results obtained showed that PZ3 blocks MMP-induced IFN-a production, although IFN induction with the synthetic TLR7 ligand R848 was unaffected (Fig.…”

Section: Endocytotic Uptake Of Mmp Is a Prerequisite For Pdc Activationmentioning

confidence: 81%

Induction of Type I IFN Is a Physiological Immune Reaction to Apoptotic Cell-Derived Membrane Microparticles

Schiller

Parčina

Heyder

et al. 2012

The Journal of Immunology

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Membrane microparticles (MMP) released from apoptotic cells deliver signals that secure the anti-inflammatory response beyond the nearest proximity of the apoptotic cell. Plasmacytoid dendritic cells (pDC) are sentinels prepared to detect cellular processes that endanger the organism. They play a key role in the regulation of both pro- and anti-inflammatory immune responses. Based on the assumption that pDC could participate in the initiation of the anti-inflammatory response to apoptotic cells, we investigated the effects of apoptotic cell-derived MMP on human pDC. The results obtained in our experiments confirmed that MMP released from apoptotic cells trigger IFN-α secretion from human pDC. They further suggest that pDC activation results from sensing of DNA contained in MMP. MMP-DNA displays a particularly strong stimulatory activity compared with MMP-RNA and other sources of DNA. Inhibition of MMP-induced IFN-α secretion by cytochalasin D, chloroquine, and an inhibitory G-rich oligodeoxynucleotide identify TLR9 as the receptor for MMP-DNA. In marked contrast to the pDC response in autoimmune patients, in healthy subjects MMP-mediated stimulation of pDC-derived IFN-α was found to be independent of FcγRIIA (CD32A). Based on our findings, we conclude that induction of pDC-derived IFN-α by MMP is a physiological event; future investigations are necessary to elucidate whether pDC activation promotes inflammation or propagates tolerance in the context of apoptotic cell clearance.

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DNA Motifs Suppressing TLR9 Responses

Cited by 33 publications

References 0 publications

Noncanonical Autophagy Is Required for Type I Interferon Secretion in Response to DNA-Immune Complexes

Noncanonical Autophagy Is Required for Type I Interferon Secretion in Response to DNA-Immune Complexes

Synthetic Oligodeoxynucleotides Containing Suppressive TTAGGG Motifs Inhibit AIM2 Inflammasome Activation

Induction of Type I IFN Is a Physiological Immune Reaction to Apoptotic Cell-Derived Membrane Microparticles

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