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• W2340906209 abstract "Recognition of DNA and RNA by endosomal and cytosolic sensors constitutes a central element in the detection of microbial invaders by the innate immune system. However, the capacity of these sensors to discriminate between microbial and endogenous nucleic acids is limited. Over the past few years, evidence has accumulated to suggest that endogenous DNA or RNA species can engage nucleic-acid-sensing pattern-recognition receptors that can trigger or sustain detrimental pathology. Here, we review principles of how the activation of innate sensors by host nucleic acids is prevented in the steady state and discuss four important determinants of whether a nucleic-acid-driven innate response is mounted. These include structural features of the ligand being sensed, the subcellular location and quantity of pathogen-derived or endogenous nucleic acids, and the regulation of sensor-activation thresholds. Furthermore, we emphasize disease mechanisms initiated by failure to discriminate self from non-self in nucleic acid detection. Recognition of DNA and RNA by endosomal and cytosolic sensors constitutes a central element in the detection of microbial invaders by the innate immune system. However, the capacity of these sensors to discriminate between microbial and endogenous nucleic acids is limited. Over the past few years, evidence has accumulated to suggest that endogenous DNA or RNA species can engage nucleic-acid-sensing pattern-recognition receptors that can trigger or sustain detrimental pathology. Here, we review principles of how the activation of innate sensors by host nucleic acids is prevented in the steady state and discuss four important determinants of whether a nucleic-acid-driven innate response is mounted. These include structural features of the ligand being sensed, the subcellular location and quantity of pathogen-derived or endogenous nucleic acids, and the regulation of sensor-activation thresholds. Furthermore, we emphasize disease mechanisms initiated by failure to discriminate self from non-self in nucleic acid detection. Our understanding of self- versus non-self-recognition by the innate immune system has come a long way since the seminal concept paper on innate immune recognition by Charles Janeway in 1989 (Janeway, 1989Janeway Jr., C.A. Approaching the asymptote? Evolution and revolution in immunology.Cold Spring Harb. Symp. Quant. Biol. 1989; 54: 1-13Crossref PubMed Google Scholar). Prior to experimental proof, Janeway proposed that invading microbes are detected by a germline-encoded pattern-recognition receptor (PRR) system that recognizes so-called pathogen-associated molecular patterns (PAMPs) as non-self. Of note, given that innocuous commensals also express PRR ligands, the more precise term microbe-associated molecular patterns (MAMPs) has since been established. MAMPs were postulated to be invariant microbial structures not present in the host and thereby serve as true non-self-patterns. This model, easily apprehensible for many microbial pathogens, which express clear non-self-structures sensed by PRRs (e.g., lipopolysaccharide recognition by MD2-TLR4), has proved to be correct and has become an integral part of our understanding of innate immunity. However, subsequent work revealed that PRRs can also be triggered by structures that are shared between microorganisms and mammals or by molecules that arise in the mammalian host under certain conditions. Thereby, the concept of clear-cut discrimination of self from non-self was questioned. A number of studies indicate that endogenous molecules released in the context of tissue or cell damage can trigger inflammation by engaging the same PRRs that have been associated with the recognition of exogenous structures. By analogy to the PAMP acronym, the term DAMP (damage-associated molecular pattern) has been coined to describe these ligands. It is now well accepted that DAMPs can initiate and perpetuate inflammatory responses in the absence of infection and that these pathways play important roles in many sterile inflammatory diseases. Of note, despite the growing list of putative DAMP molecules, not all PRRs appear to be equally involved in sensing DAMPs; in fact, some PRRs appear to be solely involved in the recognition of MAMPs (e.g., toll-like receptor 5 [TLR5]), whereas others are exclusively dedicated to damage sensing, even in the context of microbial infection (e.g., NACHT, LRR, and PYD domain-containing protein 3 [NLRP3]). In the latter scenario, the damage inflicted by microbial infection rather than by the microbe itself is detected. A heterogeneous group of PRRs detect nucleic acids (NAs). This list includes but is not limited to TLR3, TLR7–TLR9, the RNA sensors RIG-I (retinoic-acid-inducible gene I) and MDA5 (melanoma differentiation-associated protein 5), and the DNA sensors cGAS (cyclic GMP-AMP synthase) and AIM2 (absent in melanoma 2). Of note, additional NA-sensing PRRs have been described, yet further studies are required to validate their role as such. NA recognition is key in innate responses to viral infection given that NAs represent the most important viral MAMPs. Some NA-sensing PRRs appear to display limited or no selectivity for non-self DNA or RNA, which obviously calls for additional measures to render these sensors “safe” under non-infectious conditions. In this review, we discuss mechanisms that prevent recognition of endogenous NAs by PRRs under steady-state conditions and explore how these mechanisms can fail. We focus on four distinct modalities that we consider important determinants of whether a PRR triggers a response to an endogenous NA. First, along the lines of the original concept of pattern recognition, microbial NAs can feature molecular differences from endogenous DNA or RNAs that render them agonistic for a given PRR, and conversely these patterns can be suppressed or non-existent in the repertoire of endogenous NAs. We discuss these features in the section Patterns. Second, the presence of a NA in a certain compartment that is usually devoid of this class of ligands can trigger PRR activation (Location). Third, physiological amounts of an endogenous NA can be tolerated by a PRR and not induce a response, whereas a quantity exceeding a certain threshold can activate signaling (Quantity). Fourth and finally, the sensing threshold of a PRR and its signaling cascade can be subject to modulation (Threshold). Under homeostatic conditions, these modalities function in concert to control PRR activation; nevertheless, for conceptual reasons, we decided to discuss them separately in the following paragraphs. Of note, we focus exclusively on mammalian NA-sensing PRRs for which a human counterpart exists and for which robust biochemical and genetic data are available. Many studies that characterize molecular features of putative PRR ligands have been conducted in experimental systems that are influenced by determinants unrelated to the direct PRR-ligand interaction. For example, PRR-expressing cells have been transfected with different NA ligands, and activities have been assessed via measurement of cytokine release. In addition to relying on the actual physical interaction between the NA and the PRR, responses in this setup also depend on other factors such as efficiency of transfection or endocytosis, stability in endosomal compartments, binding to other proteins, cell type, etc. As such, it remains difficult to infer common structural determinants of PRR ligands from these studies. In the following paragraphs, we try to rely as much as possible on structural data to characterize the ligand repertoire for NA-sensing PRRs (Figure 1). TLR9 was the first NA-sensing PRR to be identified, and prior to its discovery, a number of studies had already provided a detailed description of NA ligands that induce cellular responses via this sensor (Krieg et al., 1995Krieg A.M. Yi A.K. Matson S. Waldschmidt T.J. Bishop G.A. Teasdale R. Koretzky G.A. Klinman D.M. CpG motifs in bacterial DNA trigger direct B-cell activation.Nature. 1995; 374: 546-549Crossref PubMed Google Scholar). TLR9 senses DNA with a certain sequence pattern, known as the CpG motif, a hexamer, containing an unmethylated CG dinucleotide flanked by a 5′ GT and a 3′ TT. Like all TLRs, TLR9 is a type I integral membrane protein, and its N-terminal leucine-rich repeat (LRR) domain forms a solenoid in a horseshoe-like shape. In general, TLR activation is achieved by dimerization of two TLR protomers; the LRR ectodomains (ECDs) face each other in a 2-fold symmetry so that the two protomers resemble the shape of an “m” from the lateral view. TLR9 is part of the subfamily of NA-sensing TLRs that encompass TLR3 and TLR7–TLR9 in the human system. These TLRs reside within the endolysosomal compartment to which they are trafficked via the chaperone protein UNC93B1 (protein unc-93 homolog B1) (Pelka et al., 2016Pelka K. Shibata T. Miyake K. Latz E. Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology.Immunol. Rev. 2016; 269: 60-75Crossref PubMed Scopus (1) Google Scholar). Within this compartment, all of these TLRs are proteolytically processed at a defined flexible loop structure that protrudes from their ECDs without disrupting the original horseshoe shape of the protomer (Bauer, 2013Bauer S. Toll-like receptor 9 processing: the key event in Toll-like receptor 9 activation?.Immunol. Lett. 2013; 149: 85-87Crossref PubMed Scopus (9) Google Scholar, Onji et al., 2013Onji M. Kanno A. Saitoh S. Fukui R. Motoi Y. Shibata T. Matsumoto F. Lamichhane A. Sato S. Kiyono H. et al.An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing.Nat. Commun. 2013; 4: 1949Crossref PubMed Google Scholar, Peter et al., 2009Peter M.E. Kubarenko A.V. Weber A.N. Dalpke A.H. Identification of an N-terminal recognition site in TLR9 that contributes to CpG-DNA-mediated receptor activation.J. Immunol. 2009; 182: 7690-7697Crossref PubMed Scopus (62) Google Scholar). This cleavage is necessary for facilitating activation of TLR signaling (Ewald et al., 2008Ewald S.E. Lee B.L. Lau L. Wickliffe K.E. Shi G.P. Chapman H.A. Barton G.M. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor.Nature. 2008; 456: 658-662Crossref PubMed Scopus (296) Google Scholar, Park et al., 2008Park B. Brinkmann M.M. Spooner E. Lee C.C. Kim Y.M. Ploegh H.L. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9.Nat. Immunol. 2008; 9: 1407-1414Crossref PubMed Scopus (268) Google Scholar). Whereas unligated TLR9 forms a monomer, binding of an agonistic ligand induces dimerization, where two CpG DNA molecules symmetrically bind two TLR9 molecules in a 2:2 stoichiometry (Ohto et al., 2015Ohto U. Shibata T. Tanji H. Ishida H. Krayukhina E. Uchiyama S. Miyake K. Shimizu T. Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9.Nature. 2015; 520: 702-705Crossref PubMed Scopus (21) Google Scholar). In this complex, one CpG DNA molecule binds to the C-terminal fragment of one protomer, as well as the CpG-binding groove in the N-terminal fragment of the other. Inhibitory DNA oligonucleotides only bind to the N-terminal fragment and therefore do not form the 2:2 activation complex. At the same time, methylated CpG single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) display much lower affinities to TLR9, and as such, they also have a lower propensity to induce TLR9 dimerization. Of note, digestion of large DNA molecules by the lysosomal endonuclease DNase II creates short TLR9-stimulatory DNA fragments (Chan et al., 2015Chan M.P. Onji M. Fukui R. Kawane K. Shibata T. Saitoh S. Ohto U. Shimizu T. Barber G.N. Miyake K. DNase II-dependent DNA digestion is required for DNA sensing by TLR9.Nat. Commun. 2015; 6: 5853Crossref PubMed Scopus (7) Google Scholar, Pawaria et al., 2015Pawaria S. Moody K. Busto P. Nündel K. Choi C.H. Ghayur T. Marshak-Rothstein A. Cutting Edge: DNase II deficiency prevents activation of autoreactive B cells by double-stranded DNA endogenous ligands.J. Immunol. 2015; 194: 1403-1407Crossref PubMed Scopus (7) Google Scholar). Although eukaryotic DNA displays a considerably lower frequency of non-methylated CpG motifs than does prokaryotic DNA, this feature does not allow faithful discrimination of self from non-self. Moreover, the phosphorothioate stabilized DNA commonly used in experimental studies is what primarily requires CpG motifs for TLR9 agonism, whereas this requirement is less strict for natural phosphodiester-linked DNA (Haas et al., 2008Haas T. Metzger J. Schmitz F. Heit A. Müller T. Latz E. Wagner H. The DNA sugar backbone 2′ deoxyribose determines toll-like receptor 9 activation.Immunity. 2008; 28: 315-323Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). Thus, it is not surprising that endogenous DNA can activate TLR9 once it is delivered into the endolysosome (see below) (Marshak-Rothstein, 2006Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease.Nat. Rev. Immunol. 2006; 6: 823-835Crossref PubMed Scopus (606) Google Scholar). The immunostimulatory activity of long double-stranded RNA (dsRNA) was recognized long before the concept of innate non-self-recognition had been established (Lampson et al., 1967Lampson G.P. Tytell A.A. Field A.K. Nemes M.M. Hilleman M.R. Inducers of interferon and host resistance. I. Double-stranded RNA from extracts of Penicillium funiculosum.Proc. Natl. Acad. Sci. USA. 1967; 58: 782-789Crossref PubMed Google Scholar). In fact, long dsRNA is not found within eukaryotic cells under normal circumstances—it represents a signature of certain virus genomes or viral replication or transcription intermediates. To this end, it fits well into the concept of non-self-recognition. TLR3 was the first bona fide PRR identified as a sensor for dsRNA (Alexopoulou et al., 2001Alexopoulou L. Holt A.C. Medzhitov R. Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.Nature. 2001; 413: 732-738Crossref PubMed Scopus (3512) Google Scholar). In contrast to other NA-sensing TLRs, considerable amounts of TLR3 are also found at the surface of certain cell types (Matsumoto et al., 2002Matsumoto M. Kikkawa S. Kohase M. Miyake K. Seya T. Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling.Biochem. Biophys. Res. Commun. 2002; 293: 1364-1369Crossref PubMed Scopus (310) Google Scholar, Pohar et al., 2013Pohar J. Pirher N. Benčina M. Manček-Keber M. Jerala R. The role of UNC93B1 protein in surface localization of TLR3 receptor and in cell priming to nucleic acid agonists.J. Biol. Chem. 2013; 288: 442-454Crossref PubMed Scopus (21) Google Scholar). TLR3 detects dsRNA that is larger than 40 bp—the ECDs of two TLR3 protomers each bind one dsRNA molecule such that their cytoplasmic C-terminal signaling domains are juxtaposed to mediate downstream signaling (Liu et al., 2008Liu L. Botos I. Wang Y. Leonard J.N. Shiloach J. Segal D.M. Davies D.R. Structural basis of toll-like receptor 3 signaling with double-stranded RNA.Science. 2008; 320: 379-381Crossref PubMed Scopus (349) Google Scholar). dsRNA recognition by TLR3 is independent of sequence in that TLR3 only interacts with the ribose-phosphate backbone. Given the absence of long dsRNA under normal conditions, there should be no role for TLR3 in the context of sterile inflammation. However, a number of studies have implicated endogenous NA recognition by TLR3 (see below), although it remains to be determined what ligand is sensed under these conditions. TLR7 and TLR8 were deorphanized as potential PRRs by their identification as receptors for immunostimulatory compounds of the imidazoquinoline family (Hemmi et al., 2002Hemmi H. Kaisho T. Takeuchi O. Sato S. Sanjo H. Hoshino K. Horiuchi T. Tomizawa H. Takeda K. Akira S. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway.Nat. Immunol. 2002; 3: 196-200Crossref PubMed Scopus (1537) Google Scholar, Jurk et al., 2002Jurk M. Heil F. Vollmer J. Schetter C. Krieg A.M. Wagner H. Lipford G. Bauer S. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848.Nat. Immunol. 2002; 3: 499Crossref PubMed Scopus (593) Google Scholar). Subsequently, it has been realized that these two closely related TLRs function as receptors for uridine-rich RNA molecules (Diebold et al., 2004Diebold S.S. Kaisho T. Hemmi H. Akira S. Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.Science. 2004; 303: 1529-1531Crossref PubMed Scopus (1768) Google Scholar, Heil et al., 2004Heil F. Hemmi H. Hochrein H. Ampenberger F. Kirschning C. Akira S. Lipford G. Wagner H. Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.Science. 2004; 303: 1526-1529Crossref PubMed Scopus (2051) Google Scholar). A number of studies have explored and compared the ligand specificities of the two TLRs in functional assays. However, this endeavor has been hampered by their mutually exclusive expression in different cell types, as well as considerable differences between mice and humans. As such, although it was shown that GU-rich sequences preferentially activate TLR7-expressing cells and that AU-rich sequences preferentially activate TLR8-positive cells, these data have to be interpreted with caution because factors independent of the TLR itself might confound these results (Forsbach et al., 2008Forsbach A. Nemorin J.G. Montino C. Müller C. Samulowitz U. Vicari A.P. Jurk M. Mutwiri G.K. Krieg A.M. Lipford G.B. Vollmer J. Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses.J. Immunol. 2008; 180: 3729-3738Crossref PubMed Google Scholar). To this end, many studies use human plasmacytoid dendritic cells (pDCs) and monocytes to compare TLR7 and TLR8, respectively. Despite their mutually exclusive expression of TLR7 and TLR8, these two cell types differ in many additional aspects that also affect TLR-mediated immune responses (e.g., uptake mechanisms, composition of endolysosomes, signaling cascades, etc.). However, with the recent elucidation of the structure of TLR8 in complex with a small-molecule agonist, as well as an “RNA-derived” ligand (Tanji et al., 2013Tanji H. Ohto U. Shibata T. Miyake K. Shimizu T. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands.Science. 2013; 339: 1426-1429Crossref PubMed Scopus (82) Google Scholar, Tanji et al., 2015Tanji H. Ohto U. Shibata T. Taoka M. Yamauchi Y. Isobe T. Miyake K. Shimizu T. Toll-like receptor 8 senses degradation products of single-stranded RNA.Nat. Struct. Mol. Biol. 2015; 22: 109-115Crossref PubMed Scopus (17) Google Scholar), we have now started to better understand this subgroup of RNA-sensing TLRs. TLR8 is also processed at its Z-loop, and under steady-state conditions, it forms a dimer, in which the Toll interleukin receptor (TIR) domains are too far apart to initiate signaling. Ligand binding induces a conformational change that brings the C termini of the protomers into close proximity, thus activating signal transduction. Interestingly, structural analyses suggest that this conformational switch can be triggered by two uridine molecules that bind at the dimerization interface (first binding site). The affinity of TLR8 toward uridine per se is low, yet binding of short oligonucleotides (ONs) at a second binding site, located at the concave surface of the ECD horseshoe structure (second binding site), greatly increases the affinity toward uridines. Of note, synthetic TLR8 agonists already trigger the formation of a signaling complex without requiring an ON engaging the second binding site (Tanji et al., 2013Tanji H. Ohto U. Shibata T. Miyake K. Shimizu T. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands.Science. 2013; 339: 1426-1429Crossref PubMed Scopus (82) Google Scholar). Whereas the second binding site accommodates ONs of different lengths and both classes of NAs, the first binding site displays a strict preference for the nucleoside uridine and, to a lesser extent, base-modified versions thereof (e.g., pseudouridine or 5-methyluridine) (Shibata et al., 2015Shibata T. Ohto U. Nomura S. Kibata K. Motoi Y. Zhang Y. Murakami Y. Fukui R. Ishimoto T. Sano S. et al.Guanosine and its modified derivatives are endogenous ligands for TLR7.Int. Immunol. 2015; (Published online October 20, 2015)https://doi.org/10.1093/intimm/dxv062Crossref Google Scholar). However, ribose-phosphorylated uridine is devoid of TLR8-agonistic activity when it is administered in conjunction with ONs (Shibata et al., 2015Shibata T. Ohto U. Nomura S. Kibata K. Motoi Y. Zhang Y. Murakami Y. Fukui R. Ishimoto T. Sano S. et al.Guanosine and its modified derivatives are endogenous ligands for TLR7.Int. Immunol. 2015; (Published online October 20, 2015)https://doi.org/10.1093/intimm/dxv062Crossref Google Scholar, Tanji et al., 2015Tanji H. Ohto U. Shibata T. Taoka M. Yamauchi Y. Isobe T. Miyake K. Shimizu T. Toll-like receptor 8 senses degradation products of single-stranded RNA.Nat. Struct. Mol. Biol. 2015; 22: 109-115Crossref PubMed Scopus (17) Google Scholar). All together, these results indicate that TLR8 is a sensor of RNA-degradation products with yet-to-be-identified nucleases and phosphatases that act upstream to generate uridine and short ONs as cognate TLR8 ligands. These results are in agreement with those of functional studies, in which uridines have been identified as a minimal prerequisite for TLR8 activation. At the same time, functional data have already implied that single-stranded RNA (ssRNA) is more potent than dsRNA in activating TLR8 (Ablasser et al., 2009bAblasser A. Poeck H. Anz D. Berger M. Schlee M. Kim S. Bourquin C. Goutagny N. Jiang Z. Fitzgerald K.A. et al.Selection of molecular structure and delivery of RNA oligonucleotides to activate TLR7 versus TLR8 and to induce high amounts of IL-12p70 in primary human monocytes.J. Immunol. 2009; 182: 6824-6833Crossref PubMed Scopus (44) Google Scholar, Sioud, 2006Sioud M. Single-stranded small interfering RNA are more immunostimulatory than their double-stranded counterparts: a central role for 2′-hydroxyl uridines in immune responses.Eur. J. Immunol. 2006; 36: 1222-1230Crossref PubMed Scopus (112) Google Scholar), which is in line with the notion that dsRNA is more nuclease resistant than ssRNA and therefore less readily yields the nucleolytic-degradation products, uridine and short ONs, required for TLR8 activation. With no structural data available, it remains to be determined how TLR7 senses RNA. A recent study suggested that the mode of activation of TLR8 can be partly extrapolated to TLR7 (Shibata et al., 2015Shibata T. Ohto U. Nomura S. Kibata K. Motoi Y. Zhang Y. Murakami Y. Fukui R. Ishimoto T. Sano S. et al.Guanosine and its modified derivatives are endogenous ligands for TLR7.Int. Immunol. 2015; (Published online October 20, 2015)https://doi.org/10.1093/intimm/dxv062Crossref Google Scholar). As such, it has been demonstrated that TLR7 could also be activated by a combination of a short polynucleotide and a single nucleoside. In contrast to TLR8, TLR7 showed high binding affinity toward guanosines but no other canonical nucleoside when it was combined with ONs. These results parallel functional data from testing these combinations on TLR7-expressing cells. Although these results indirectly suggest that TLR7 also entertains two binding sites, corroborating this model requires additional data. The mere presence of uridines and guanosines does not qualify as a specific non-self-signature, even though it has been suggested that certain pathogens display a greater proportion of uridine within their RNA at nuclease-accessible sites (Geyer et al., 2015Geyer M. Pelka K. Latz E. Synergistic activation of Toll-like receptor 8 by two RNA degradation products.Nat. Struct. Mol. Biol. 2015; 22: 99-101Crossref PubMed Scopus (2) Google Scholar). Additional features must be at play to discriminate self from non-self. In fact, endogenous RNAs are posttranscriptionally modified at their nucleobases and backbones, and these modifications greatly decrease TLR-stimulatory activity (Karikó et al., 2005Karikó K. Buckstein M. Ni H. Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA.Immunity. 2005; 23: 165-175Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar). Most prominently, 2′-O-methylation of uridines strongly abolishes the TLR7 and TLR8 agonistic activity of RNA molecules (Karikó et al., 2005Karikó K. Buckstein M. Ni H. Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA.Immunity. 2005; 23: 165-175Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar). 2′-O-methylated RNAs are more resistant to nucleolytic degradation, an important step upstream of TLR8 and possibly TLR7 (see above). On the other hand, these modifications might also directly interfere with the binding to these TLRs. Interestingly, the presence of modified nucleosides not only abolishes the intrinsic activity of a given RNA molecule but also competitively inhibits agonistic activity of unmodified NAs (Robbins et al., 2007Robbins M. Judge A. Liang L. McClintock K. Yaworski E. MacLachlan I. 2′-O-methyl-modified RNAs act as TLR7 antagonists.Mol. Ther. 2007; 15: 1663-1669Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). As such, modified endogenous RNAs could regulate the receptor activation threshold for agonistic TLR7 or TLR8 ligands. The presence of such modifications can in part explain the lack of immunostimulation of selected host-derived RNA molecules in comparison to that of their microbial counterparts (e.g., individual tRNAs) (Gehrig et al., 2012Gehrig S. Eberle M.E. Botschen F. Rimbach K. Eberle F. Eigenbrod T. Kaiser S. Holmes W.M. Erdmann V.A. Sprinzl M. et al.Identification of modifications in microbial, native tRNA that suppress immunostimulatory activity.J. Exp. Med. 2012; 209: 225-233Crossref PubMed Scopus (34) Google Scholar, Jöckel et al., 2012Jöckel S. Nees G. Sommer R. Zhao Y. Cherkasov D. Hori H. Ehm G. Schnare M. Nain M. Kaufmann A. Bauer S. The 2′-O-methylation status of a single guanosine controls transfer RNA-mediated Toll-like receptor 7 activation or inhibition.J. Exp. Med. 2012; 209: 235-241Crossref PubMed Scopus (26) Google Scholar). However, endogenous RNA derived from apoptotic or dying cells still activates TLR7 and TLR8 once it is delivered into endolysosomes (Ganguly et al., 2009Ganguly D. Chamilos G. Lande R. Gregorio J. Meller S. Facchinetti V. Homey B. Barrat F.J. Zal T. Gilliet M. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8.J. Exp. Med. 2009; 206: 1983-1994Crossref PubMed Scopus (257) Google Scholar, Marshak-Rothstein, 2006Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease.Nat. Rev. Immunol. 2006; 6: 823-835Crossref PubMed Scopus (606) Google Scholar, Vollmer et al., 2005Vollmer J. Tluk S. Schmitz C. Hamm S. Jurk M. Forsbach A. Akira S. Kelly K.M. Reeves W.H. Bauer S. Krieg A.M. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8.J. Exp. Med. 2005; 202: 1575-1585Crossref PubMed Scopus (335) Google Scholar). Thus, as for TLR9, additional factors need to be at play to allow faithful discrimination of self from non-self by TLR7 and TLR8 (see below). In addition to TLR-mediated sensing of NAs in endosomal compartments, the cytosol is also under monitoring for microbial NAs. With the availability of TLR9-deficient mice, it has been realized that additional TLR9-independent, cytosolic DNA-sensing pathways must exist. To this end, it has been noted that cytosolic delivery of dsDNA, but not ssDNA, readily induces antiviral gene expression in cells devoid of TLR9 (Hornung and Latz, 2010Hornung V. Latz E. Intracellular DNA recognition.Nat. Rev. Immunol. 2010; 10: 123-130Crossref PubMed Scopus (164) Google Scholar). Phosphothioate stabilization of the DNA backbone, which is commonly used to activate TLR9, greatly reduces the activity of this cytosolic DNA response (Stetson and Medzhitov, 2006Stetson D.B. Medzhitov R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response.Immunity. 2006; 24: 93-103Abstract Full Text Full Text PDF PubMed Scopus (563) Google Scholar). Furthermore, models of TLR9-independent sterile inflammation suggest the existence of a cytosolic DNA-sensing pathway (Okabe et al., 2005Okabe Y. Kawane K. Akira S. Taniguchi T. Nagata S. Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation.J. Exp. Med. 2005; 202: 1333-1339Crossref PubMed Scopus (188) Google Scholar, Stetson et al., 2008Stetson D.B. Ko J.S. Heidmann T. Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity.Cell. 2008; 134: 587-598Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar). It has now become clear that the majority of this response is mediated by the cGAS-cGAMP-STING signaling cascade (Cai et al., 2014Cai X. Chiu Y.H. Chen Z.J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling.Mol. Cell. 2014; 54: 289-296Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, Hornung et al., 2014Hornung V. Hartmann R. Ablasser A. Hopfner K.P. OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids.Nat. Rev. Immunol. 2014; 14: 521-528Crossref PubMed Scopus (36) Google Scholar), in" @default.
• W2340906209 created "2016-06-24" @default.
• W2340906209 creator A5016667606 @default.
• W2340906209 creator A5062546114 @default.
• W2340906209 creator A5064673147 @default.
• W2340906209 date "2016-04-01" @default.
• W2340906209 modified "2023-10-18" @default.
• W2340906209 title "Recognition of Endogenous Nucleic Acids by the Innate Immune System" @default.
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