Endosomal Translocation of Vertebrate DNA Activates Dendritic Cells via TLR9-Dependent and -Independent Pathways

Yasuda, Kei; Yu, Philipp; Kirschning, Carsten J.; Schlatter, Beatrix; Schmitz, Frank; Heit, Antje; Bauer, Stefan; Hochrein, Hubertus; Wagner, Hermann

doi:10.4049/jimmunol.174.10.6129

Cited by 238 publications

(213 citation statements)

References 44 publications

(63 reference statements)

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“…Only pDC sensed bacterial RNA via TLR7, whereas myeloid dendritic cells and somatic cells recognized bacterial RNA independently of TLR and RIG-like receptors. Besides recognition by the NALP3 inflammasome, we provide strong evidence for the existence of a further cytosolic RNA receptor that is triggered by bacterial RNA and is widely expressed in different cell types, paralleling previous findings for bacterial DNA [21,22].…”

Section: Introductionsupporting

confidence: 70%

Bacterial RNA is recognized by different sets of immunoreceptors

et al. 2009

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Innate immunity recognizes microbial nucleic acids by endosomal TLR and cytosolic recognition systems. Despite increasing knowledge on the properties of nucleic acid recognition for viral RNA and bacterial DNA, little is known about the immunogenicity of prokaryotic RNA. Here we show that bacterial RNA is a potent trigger for type-I IFN secretion in human PBMC. Activation of human plasmacytoid dendritic cells was dependent on endosomal maturation and could be blocked by a TLR7-specific inhibitor. Murine plasmacytoid dendritic cells from TLR7-deficient mice were unresponsive to bacterial RNA. Surprisingly, in myeloid DC, TLR were dispensable for TNF-a and IL-12 induction by bacterial RNA. Even non-immune stroma cells were able to mount a NF-jB response upon triggering with bacterial RNA. Retinoic-acid inducible gene I and melanoma-differentiation-associated gene 5 could be ruled out to be responsible for this reactivity. Although the inflammasome adaptor protein, apoptosis-associated speck-like protein, and a functional type-I IFN receptor were necessary for IL-1b secretion in myeloid DC, these proteins were dispensable for TNF-a and IL-12 induction by cytosolic bacterial RNA. Our results show that besides of activation of TLR7 and inflammasomes, bacterial RNA activates additional cytosolic receptors similarly as has been reported for recognition of bacterial DNA.Key words: Host defense . Immunology . Inflammation IntroductionInnate immunity relies on germline-encoded PRR, which sense conserved microbial structures of non-host origin. The bestdescribed class of PRR is the TLR. Most TLR sense pathogen components on the cell surface but a subset of TLR (TLR3,7, 8 and 9) have been shown to detect nucleic acids in the endosomal compartment [1][2][3]. Besides unmethylated CpG-DNA, which is the ligand for TLR9 [4], viral RNA was identified as a ligand for nucleic acid detecting TLR. TLR3 detects double-stranded RNA [5]. RNA-oligonucleotides as well as viral RNA are also recognized by TLR7 [6,7], especially in plasmacytoid dendritic cells (pDC). The quality and the extent of nucleotide modifications are critical for recognition by these receptors [8]. Importantly, host-derived RNA shows a much higher frequency of RNA modifications than RNA derived from prokaryotic sources [8]. Nucleic acid modifications therefore represent a structural feature, which enables the immune system to distinguish self from non-self RNA. Additionally, GU-and U-rich sequence motives were identified to play a role in TLR7-and TLR8-mediated recognition [6,9,10]. In general, TLR triggering in innate immune cells results in a strong NF-kB response. Exceptionally, TLR 7 and 9 signaling in pDC also leads to an IFN-regulatory factor 7 (IRF7) activation, resulting in type-I IFN secretion [11].The cytosolic RNA helicases retinoic-acid inducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA5) A third class of innate immune receptors is the cytosolic NODlike receptors. Particularly, NACHT-, LRR-and pyrin domaincontaining protein 3 (...

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Section: Introductionsupporting

confidence: 70%

Bacterial RNA is recognized by different sets of immunoreceptors

et al. 2009

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“…4, A and B). TLR9-independent effects of natural phosphodiester DNA on immune cells have also been reported, but these effects were also independent of the CpG motif (40,41). Thus, to our knowledge, TLR9 is required for all CpG-dependent effects of DNA on immune cells.…”

Section: Discussionmentioning

confidence: 90%

CpG DNA Activates Survival in Murine Macrophages through TLR9 and the Phosphatidylinositol 3-Kinase-Akt Pathway

Sester

Brion

Trieu

et al. 2006

The Journal of Immunology

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Bacterial CpG-containing (CpG) DNA promotes survival of murine macrophages and triggers production of proinflammatory mediators. The CpG DNA-induced inflammatory response is mediated via TLR9, whereas a recent study reported that activation of the Akt prosurvival pathway occurs via DNA-dependent protein kinase (DNA-PK) and independently of TLR9. We show, in this study, that Akt activation and survival of murine bone marrow-derived macrophages (BMM) triggered by CpG-containing phosphodiester oligodeoxynucleotides or CpG-containing phosphorothioate oligodeoxynucleotides was completely dependent on TLR9. In addition, survival triggered by CpG-containing phosphodiester oligodeoxynucleotides was not compromised in BMM from SCID mice that express a catalytically inactive form of DNA-PK. CpG DNA-induced survival of BMM was inhibited by the PI3K inhibitor, LY294002, but not by the MEK1/2 inhibitor, PD98059. The effect of LY294002 was specific to survival, because treatment of BMM with LY294002 affected CpG DNA-induced TNF-α production only modestly. Therefore, CpG DNA activates macrophage survival via TLR9 and the PI3K-Akt pathway and independently of DNA-PK and MEK-ERK.

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“…, and control WT mice, all on a C57Bl/6 background, were housed under specific pathogen-free conditions (32)(33)(34)(35)(36).…”

Section: Methodsmentioning

confidence: 99%

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Gratz

Siller

Schaljo

et al. 2008

Journal of Biological Chemistry

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Bacterial pathogens are recognized by the innate immune system through pattern recognition receptors, such as Toll-like receptors (TLRs). Engagement of TLRs triggers signaling cascades that launch innate immune responses. Activation ofMAPKs and NF-B, elements of the major signaling pathways induced by TLRs, depends in most cases on the adaptor molecule MyD88. In addition, Gram-negative or intracellular bacteria elicit MyD88-independent signaling that results in production of type I interferon (IFN). Here we show that in mouse macrophages, the activation of MyD88-dependent signaling by the extracellular Gram-positive human pathogen group A streptococcus (GAS; Streptococcus pyogenes) does not require TLR2, a receptor implicated in sensing of Gram-positive bacteria, or TLR4 and TLR9. Redundant engagement of either of these TLR molecules was excluded by using TLR2/4/9 triple-deficient macrophages. We further demonstrate that infection of macrophages by GAS causes IRF3 (interferon-regulatory factor 3)-dependent, MyD88-independent production of IFN. Surprisingly, IFN is induced also by GAS lacking slo and sagA, the genes encoding cytolysins that were shown to be required for IFN production in response to other Gram-positive bacteria. Our data indicate that (i) GAS is recognized by a MyD88-dependent receptor other than any of those typically used by bacteria, and (ii) GAS as well as GAS mutants lacking cytolysin genes induce type I IFN production by similar mechanisms as bacteria requiring cytoplasmic escape and the function of cytolysins.Group A streptococcus (GAS 4 ; Streptococcus pyogenes) is an important human Gram-positive pathogen responsible for a wide spectrum of infections, ranging from mild diseases (e.g. tonsillitis) to serious illness (e.g. necrotizing fasciitis, sepsis, or severe poststreptococcal sequelae) (1). The persistence of GAS in the human population and the severity of some GAS diseases are the result of activities of a number of virulence factors that enable the pathogen to escape immune surveillance or, on contrary, induce an overreaction of the immune system (2, 3). Although GAS is generally regarded as an extracellular pathogen, recent findings suggest that GAS can survive (although not multiply) within various host cells, such as neutrophils, macrophages, epithelial cells, and fibroblasts (4 -7). The surviving bacteria may serve as a reservoir for recurrent GAS diseases.Immune responses to bacteria are initiated by recognition of bacterial components called pathogen-associated molecular patterns through host cell-encoded pattern recognition receptors (PRRs) (8, 9). Typically, pathogen-associated molecular patterns are components of the bacterial cell wall (e.g. lipopolysaccharide and lipoteichoic acid), but they may also be derived from the inside of bacteria (e.g. DNA). The primary function of PRRs is to trigger signaling cascades that activate antimicrobial defense programs. The best studied class of PRRs is the Toll-like receptor (TLR) family, which consists of 13 transmembrane glycoprote...

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Endosomal Translocation of Vertebrate DNA Activates Dendritic Cells via TLR9-Dependent and -Independent Pathways

Cited by 238 publications

References 44 publications

Bacterial RNA is recognized by different sets of immunoreceptors

Bacterial RNA is recognized by different sets of immunoreceptors

CpG DNA Activates Survival in Murine Macrophages through TLR9 and the Phosphatidylinositol 3-Kinase-Akt Pathway

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

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