DNase II-dependent DNA digestion is required for DNA sensing by TLR9

Chan, Mei Po; Onji, Masahiro; Fukui, Ryutaro; Kawane, Kohki; Shibata, Takuma; Saitoh, Shu‐ichi; Ohto, Umeharu; Shimizu, Toshiyuki; Barber, Glen N.; Miyake, Kensuke

doi:10.1038/ncomms6853

Cited by 113 publications

(94 citation statements)

References 28 publications

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“…Noteworthy, it has been shown that inflammasome activation by shorter DNA fragments was stronger than by longer fragments (Dombrowski et al, 2011). Also, the DNase IImediated digestion of genomic DNA into short oligonucleotides is required for endosomal sensing by TLR9 (Chan et al, 2015). Furthermore, in support of an important role for DNA processing in the regulation of immune responses, it has been reported that a lack of DNA degradation by the caspase-activated DNase (CAD), which is responsible for the cell-…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 97%

The Exonuclease Trex2 Shapes Psoriatic Phenotype

Manils

Casas

Viña-Vilaseca

et al. 2016

Journal of Investigative Dermatology

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Trex2 is a keratinocyte-specific 3'-deoxyribonuclease that participates in the maintenance of skin homeostasis after DNA damage. Here, we show that this exonuclease is strongly upregulated in human psoriasis, a hyperproliferative and inflammatory skin disease. Similarly, the imiquimod (IMQ)- and Il23-induced mouse psoriasis was associated with a substantial upregulation of Trex2, which was recruited into fragmented chromatin in keratinocytes that were undergoing impaired proliferation, differentiation, and cell death, indicating an important role in DNA processing. Using Trex2 knockout mice, we have found that Trex2 deficiency attenuated IMQ-induced psoriasis-like skin inflammation and enhanced IMQ-induced parakeratosis. Also, Il23-induced ear swelling was diminished in Trex2 knockout mice in comparison with wild-type (wt) mice. Transcriptome analysis identified multiple genes that were deregulated by Trex2 loss after treatment with IMQ. Specifically, immune response genes and pathways normally associated with inflammation were downregulated, whereas those related to skin differentiation and chromatin biology showed increased expression. Interestingly, Trex2 deficiency led to decreased IMQ-induced keratinocyte death via both cell autonomous and noncell autonomous mechanisms. Hence, our data indicate that Trex2 acts as a critical factor in the pathogenesis of psoriasis by promoting keratinocyte apoptosis and enucleation and thereby influencing skin immune responses.

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Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 97%

The Exonuclease Trex2 Shapes Psoriatic Phenotype

Manils

Casas

Viña-Vilaseca

et al. 2016

Journal of Investigative Dermatology

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“…In pDCs, the ODNs induce secretion of TNF-a and IL-12. The synthesis of type I IFNs is primarily linked to the A class ODNs (10,20,21), because of the different cellular internalization pathway (25). The B class ODNs captured to nanobeads or cationic lipids trigger IFN-a synthesis in pDCs (32,33), which implies that the propensity of ODNs to internalize into early endosomes, rather than DNA sequence itself, drives MyD88/IRF7-dependent signaling and the IFN-a synthesis (34).…”

Section: Discussionmentioning

confidence: 99%

“…After processing dsDNA with endosomal DNAse II shorter fragments of ssDNA are generated, which than may serve as TLR9 ligands (25). To prevent the degradation of ODNs by nucleases, synthetic ODNs may consist of a partial or complete PTO backbone.…”

Section: Response Of Mouse Dcs To the Minm Odnmentioning

confidence: 99%

“…The A, C, and P class (23,24) CpG ODNs form intra-and intermolecular duplexes. These multi-ODN structures are suggested to take different routes of endocytosis and therefore induce synthesis of type I IFNs (23,25,26). For activation of mouse TLR9 with A class ODNs, endosomal DNase II has to cleave the A class ODNs, which consequently leads to the formation of short ODN fragments resembling B type ODN (25).…”

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confidence: 99%

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Species-Specific Minimal Sequence Motif for Oligodeoxyribonucleotides Activating Mouse TLR9

Pohar

Lainšček

Fukui

et al. 2015

The Journal of Immunology

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Synthetic oligodeoxyribonucleotides (ODNs) containing unmethylated CpG recapitulate the activation of TLR9 by microbial DNA. ODNs are potent stimulators of the immune response in cells expressing TLR9. Despite extensive use of mice as experimental animals in basic and applied immunological research, the key sequence determinants that govern the activation of mouse TLR9 by ODNs have not been well defined. We performed a systematic investigation of the sequence motif of B class phosphodiester ODNs to identify the sequence properties that govern mouse TLR9 activation. In contrast to ODNs activating human TLR9, where the minimal sequence motif for the receptor activation comprises a pair of closely positioned CpGs we found that the mouse TLR9 requires a single CpG positioned 4–6 nt from the 5′-end. Activation is augmented by a 5′TCC sequence one to three nucleotides from the CG. The distance of the CG dinucleotide of four to six nucleotides from the 5′-end and the ODN’s length fine-tunes activation of mouse macrophages. Length of the ODN <23 and >29 nt decreases activation of dendritic cells. The ODNs with minimal sequence induce Th1-type cytokine synthesis in dendritic cells and confirm the expression of cell surface markers in B cells. Identification of the minimal sequence provides an insight into the sequence selectivity of mouse TLR9 and points to the differences in the receptor selectivity between species probably as a result of differences in the receptor binding sites.

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“…Thus, TLR8 might also sense bacterial RNA degradation products. The concept of recognition of RNA degradation products by TLR8 raises the hypothesis that phosphatases and/or nucleases of bacterial or host origin might play a role upstream of TLR8 activation (45), in analogy to the requirement for lysosomal endonuclease DNase II for the activation of TLR9 (46,47).…”

Section: Tatjana Eigenbrod and Alexander H Dalpkementioning

confidence: 99%

Bacterial RNA: An Underestimated Stimulus for Innate Immune Responses

Eigenbrod

Dalpke

2015

The Journal of Immunology

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Although DNA of bacterial and viral origin, as well as viral RNA, have been intensively studied as triggers of innate immune responses, the stimulatory properties of bacterial RNA and its role during infections have just begun to be deciphered. Bacterial RNA is a strong inducer of type I IFN and NF-κB–dependent cytokines, and it also can activate the Nlrp3 inflammasome. In this review, we focus on the receptors and signaling pathways involved in innate immune activation by bacterial RNA and analyze the physiological relevance of bacterial RNA recognition during infections. Furthermore, we present the concept that RNA modifications can impair RNA-dependent immune activation. RNA modifications differ between eukaryotes and prokaryotes; thus, they can serve to define the innate pattern that is recognized. In this regard, we discuss the role of ribose 2′-O-methylation as a potential immune-escape mechanism.

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DNase II-dependent DNA digestion is required for DNA sensing by TLR9

Cited by 113 publications

References 28 publications

The Exonuclease Trex2 Shapes Psoriatic Phenotype

The Exonuclease Trex2 Shapes Psoriatic Phenotype

Species-Specific Minimal Sequence Motif for Oligodeoxyribonucleotides Activating Mouse TLR9

Bacterial RNA: An Underestimated Stimulus for Innate Immune Responses

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