Cited by 6,491Immune Response and InflammationImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.

A Toll-like receptor recognizes bacterial DNA

Hemmi, Hiroaki, Takeuchi, Osamu, Kawai, Taro, Kaisho, Tsuneyasu, Sato, Shintaro, Sanjo, Hideki, Matsumoto, Makoto, Hoshino, Katsuaki, Wagner, Hermann, Takeda, Kiyoshi, Akira, Shizuo·2000·Nature

DOI 10.1038/35047123

Open this paper in CoChat — free account

Abstract

DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.

Integrity signals

Registry

Crossref · 10.1038/35047123

Cites

33 of 33 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
Poltorak, A., He, X., Smirnova, I., Liu, M.-Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998) · Science · doi:10.1126/science.282.5396.2085 · Cited by 7,631
A human homologue of the Drosophila Toll protein signals activation of adaptive immunity
Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A. J. (1997) · Nature · doi:10.1038/41131 · Cited by 6,137
Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components.
Takeuchi, O., Hoshino, K., Kawai, T., Sanjo, H., Takada, H., Ogawa, T., Takeda, K., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80119-3 · Cited by 3,680
Self-citation
CpG motifs in bacterial DNA trigger direct B-cell activation
Krieg, A. M., Yi, A.-K., Matson, S., Waldschmidt, T. J., Bishop, G. A., Teasdale, R., Koretzky, G. A., & Klinman, D. M. (1995) · Nature · doi:10.1038/374546a0 · Cited by 3,508
Cutting Edge: Toll-Like Receptor 4 (TLR4)-Deficient Mice Are Hyporesponsive to Lipopolysaccharide: Evidence for TLR4 as the Lps Gene Product
Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., & Akira, S. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.7.3749 · Cited by 3,374
Self-citation
Innate Immunity: The Virtues of a Nonclonal System of Recognition
Medzhitov, R., & Janeway, C. A. (1997) · Cell · doi:10.1016/s0092-8674(00)80412-2 · Cited by 2,434
Unresponsiveness of MyD88-deficient mice to endotoxin.
Kawai, T., Adachi, O., Ogawa, T., Takeda, K., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80086-2 · Cited by 2,367
Self-citation
A family of human receptors structurally related to Drosophila Toll.
Rock, F., Hardiman, G., Timans, J., Kastelein, R., & Bazan, J. (1998) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.95.2.588 · Cited by 2,009
Host Defense Mechanisms Triggered by Microbial Lipoproteins Through Toll-Like Receptors
Brightbill, H. D., Libraty, D. H., Krutzik, S. R., Yang, R., Belisle, J. T., Bleharski, J. R., Maitland, M. L., Norgard, M. V., Plevy, S. E., Smale, S. T., et al. (1999) · Science · doi:10.1126/science.285.5428.732 · Cited by 1,659
Cell Activation and Apoptosis by Bacterial Lipoproteins Through Toll-like Receptor-2
Aliprantis, A. O., Yang, R., Mark, M. R., Suggett, S., Devaux, B., Radolf, J. D., Klimpel, G. R., Godowski, P. J., & Zychlinsky, A. (1999) · Science · doi:10.1126/science.285.5428.736 · Cited by 1,463

Flagged first, then by citations

Show all 33 references

Sorted by citations

Items 601–700 of 1,045

Antisense therapy in oncology: new hope for an old idea?
Tamm, I., Dörken, B., & Hartmann, G. (2001) · The Lancet · doi:10.1016/s0140-6736(01)05629-x · Cited by 229
Association of β-arrestin and TRAF6 negatively regulates Toll-like receptor–interleukin 1 receptor signaling
Wang, Y., Tang, Y., Teng, L., Wu, Y., Zhao, X., & Pei, G. (2005) · Nature Immunology · doi:10.1038/ni1294 · Cited by 235
“CpG oligodeoxynucleotide was synthesized as describe”
Toll-like Receptor-2 Mediates Treponema Glycolipid and Lipoteichoic Acid-induced NF-κB Translocation
Opitz, B., Schröder, N. W. J., Spreitzer, I., Michelsen, K. S., Kirschning, C. J., Hallatschek, W., Zähringer, U., Härtung, T., Göbel, U. B., & Schumann, R. R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010481200 · Cited by 228
Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer
Gaiser, R. A., Halimi, A., Alkharaan, H., Lu, L., Davanian, H., Healy, K., Hugerth, L. W., Ateeb, Z., Valente, R., Fernández Moro, C., et al. (2019) · Gut · doi:10.1136/gutjnl-2018-317458 · Cited by 227
Pattern recognition receptors in innate immunity, host defense, and immunopathology
Suresh, R., & Mosser, D. M. (2013) · AJP Advances in Physiology Education · doi:10.1152/advan.00058.2013 · Cited by 250
“During erythropoiesis, nuclei/DNA are normally ejected and subsequently degraded by enzymes like DNAseI and 3=-repair exonuclease 1 (Trex1) (41, 45).”
BackgroundInfluential
Histones, DNA, and Citrullination Promote Neutrophil Extracellular Trap Inflammation by Regulating the Localization and Activation of TLR4
Tsourouktsoglou, T.-D., Warnatsch, A., Ιωάννου, Μ., Hoving, D., Wang, Q., & Papayannopoulos, V. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107602 · Cited by 227
Involvement of the Toll-Like Receptor 9 Signaling Pathway in the Induction of Innate Immunity by Baculovirus
Abe, T., Hemmi, H., Miyamoto, H., Moriishi, K., Tamura, S., Takaku, H., Akira, S., & Matsuura, Y. (2005) · Journal of Virology · doi:10.1128/jvi.79.5.2847-2858.2005 · Cited by 225
“taining unmethylated CpG motifs, respectively (21, 24, 27, 46).”
BackgroundMethodInfluentialSelf-citation
RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA
Sirois, C. M., Jin, T., Miller, A. L., Bertheloot, D., Nakamura, H., Horvath, G. L., Mian, A., Jiang, J., Schrum, J. E., Bossaller, L., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20120201 · Cited by 234
“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).”
Background
Microbial Recognition Via Toll-Like Receptor-Dependent and -Independent Pathways Determines the Cytokine Response of Murine Dendritic Cell Subsets to CD40 Triggering
Edwards, A. D., Manickasingham, S. P., Spörri, R., Diebold, S. S., Schulz, O., Sher, A., Kaisho, T., Akira, S., & Sousa, C. R. E. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.7.3652 · Cited by 229
Self-citation
TLR7 and TLR9 in SLE: when sensing self goes wrong
Celhar, T., Magalhães, R., & Fairhurst, A. (2012) · Immunologic Research · doi:10.1007/s12026-012-8270-1 · Cited by 234
“Stimulation results in cytokine secretion, proliferation, or maturation [79–81].”
Background
Insights from advances in research of chemically induced experimental models of human inflammatory bowel disease
Kawada, M. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i42.5581 · Cited by 223
Intact Gram-NegativeHelicobacter pylori,Helicobacter felis, andHelicobacter hepaticusBacteria Activate Innate Immunity via Toll-Like Receptor 2 but Not Toll-Like Receptor 4
Mandell, L., Moran, A. P., Cocchiarella, A., Houghton, J., Taylor, N. S., Fox, J. G., Wang, T. C., & Kurt‐Jones, E. A. (2004) · Infection and Immunity · doi:10.1128/iai.72.11.6446-6454.2004 · Cited by 231
“Recent data also indicate that TLRs are important in the innate immune response to bacterial DNA (TLR9 [24])”
Background
CpG-Depleted Plasmid DNA Vectors with Enhanced Safety and Long-Term Gene Expression in Vivo
Yew, N. S., Zhao, H., Przybylska, M., Wu, I., Tousignant, J. D., Scheule, R. K., & Cheng, S. H. (2002) · Molecular Therapy · doi:10.1006/mthe.2002.0598 · Cited by 221
Innate immune recognition of, and regulation by, DNA
Ishii, K. J., & Akira, S. (2006) · Trends in Immunology · doi:10.1016/j.it.2006.09.002 · Cited by 222
Self-citation
The PYHIN protein family as mediators of host defenses
Schattgen, S., & Fitzgerald, K. A. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01053.x · Cited by 224
“Recognition of DNA is dependent on TLR9, which is localized to the endosomal compartment and is expressed in B cells and plasmacytoid dendritic cells (pDCs), and recognizes hypomethylated CpG-rich DNA (3).”
Background
Toll-Like Receptor 9 Agonists Promote Cellular Invasion by Increasing Matrix Metalloproteinase Activity
Merrell, M. A., Ilvesaro, J. M., Lehtonen, N., Sorsa, T. A., Gehrs, B. C., Rosenthal, E. L., Chen, D., Shackley, B., Harris, K. W., & Selander, K. S. (2006) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0007 · Cited by 222
“CpG dinucleotides mimic the immunostimulatory activity of bacterial DNA in vertebrates and are also recognized by TLR9 (3-6).”
Background
SIGIRR Inhibits Interleukin-1 Receptor- and Toll-like Receptor 4-mediated Signaling through Different Mechanisms
Qin, J., Qian, Y., Yao, J., Cui, G., & Li, X. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501363200 · Cited by 227
Important aspects of Toll-like receptors, ligands and their signaling pathways
Chang, Z. L. (2010) · Inflammation Research · doi:10.1007/s00011-010-0208-2 · Cited by 228
Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection
Barnes, B. J., Richards, J. O., Mancl, M. E., Hanash, S., Beretta, L., & Pitha, P. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400726200 · Cited by 223
TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target
Ullah, M. O., Sweet, M. J., Mansell, A. S., Kellie, S., & Kobe, B. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.2ri1115-531r · Cited by 232
Intracellular Nucleic Acid Detection in Autoimmunity
Crowl, J. T., Gray, E. E., Pestal, K., Volkman, H. E., & Stetson, D. B. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052331 · Cited by 222
“inflammatory and antiviral response dates back to the year 2000, when Akira and colleagues reported that Toll-like receptor 9 (TLR9) is activated by DNA (5).”
Background
The origin and properties of extracellular DNA: From PAMP to DAMP
Pisetsky, D. S. (2012) · Clinical Immunology · doi:10.1016/j.clim.2012.04.006 · Cited by 231
“The demonstration of CpG DNA’s activity as a PAMP led rapidly to the discovery to TLR9 as a key DNA sensor in B cells, dendritic cells and macrophages and the critical role of MyD88 as a downstream signaling element [54,55].”
Background
TLR7-dependent and FcγR-independent production of type I interferon in experimental mouse lupus
Lee, P. Y., Kumagai, Y., Li, Y., Takeuchi, O., Yoshida, H., Weinstein, J. S., Kellner, E. S., Nacionales, D. C., Barker, T. T., Kelly‐Scumpia, K. M., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20080462 · Cited by 220
Self-citation
Involvement of TLR2 and TLR4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter
Shoenfelt, J. L., Mitkus, R. J., Zeisler, R. L., Spatz, R. O., Powell, J., Fenton, M. J., Squibb, K. A., & Medvedev, A. E. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.1008587 · Cited by 230
Identification and characterization of a functional, alternatively spliced Toll‐like receptor 7 (TLR7) and genomic disruption of TLR8 in chickens
Philbin, V. J., Iqbal, M., Boyd, Y., Goodchild, M. J., Beal, R. K., Bumstead, N., Young, J. R., & Smith, A. L. (2005) · Immunology · doi:10.1111/j.1365-2567.2005.02125.x · Cited by 222
The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors
Alexander, S. P. H., Benson, H. E., Faccenda, E., Pawson, A. J., Sharman, J. L., Spedding, M., Peters, J. A., Harmar, A. J., & Collaborators, C. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12449 · Cited by 222
Recognition of bacterial infection by innate immune sensors
Kumar, S., Ingle, H., Prasad, D. V. R., & Kumar, H. (2012) · Critical Reviews in Microbiology · doi:10.3109/1040841x.2012.706249 · Cited by 232
“The bacterial DNA or CpG motifs serve as a PAMP for TLR9, which is located on the endosomal membrane (Hemmi et al. 2000).”
A Promiscuous Lipid-Binding Protein Diversifies the Subcellular Sites of Toll-like Receptor Signal Transduction
Bonham, K. S., Orzalli, M. H., Hayashi, K., Wolf, A. I., Glanemann, C., Weninger, W., Iwasaki, A., Knipe, D. M., & Kagan, J. C. (2014) · Cell · doi:10.1016/j.cell.2014.01.019 · Cited by 232
“First, it is the best-characterized endosome-localized TLR (Barbalat et al., 2011), and its ligand (unmethylated CpGcontaining DNA) is easy to produce (Hemmi et al., 2000).”
Background
Plasmacytoid dendritic cells: key players in the initiation and regulation of immune responses
Lande, R., & Gilliet, M. F. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05152.x · Cited by 240
Tumor-derived exosomes: a new source of tumor rejection antigens
André, F., Schartz, N., Chaput, N., Flament, C., Raposo, G., Amigorena, S., Angevin, E., & Zitvogel, L. (2002) · Vaccine · doi:10.1016/s0264-410x(02)00384-5 · Cited by 225
Lipocalin 2 Is Required for Pulmonary Host Defense against Klebsiella Infection
Chan, Y. R., Liu, J. S., Pociask, D. A., Zheng, M., Mietzner, T. A., Berger, T., Mak, T. W., Clifton, M. C., Strong, R. K., Ray, P., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803282 · Cited by 219
NK- and CD8+ T Cell-Mediated Eradication of Established Tumors by Peritumoral Injection of CpG-Containing Oligodeoxynucleotides
Kawarada, Y., Ganß, R., Garbi, N., Sacher, T., Arnold, B., & Hämmerling, G. J. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.9.5247 · Cited by 222
“Bacterial unmethylated cytosine-phosphorothioate-guanine (CpG)-rich oligodeoxynucleotides (CpG-ODN) are potent activators of innate immunity and induce cellular response mediated by Toll-like receptor 9 (23) Thus, CpG-ODN are strong inducers of NK cells (24), probably through induction of IL-12 (25, 26).”
Background
Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions
Dzionek, A., Inagaki, Y., Okawa, K., Nagafune, J., Röck, J., Sohma, Y., Winkels, G., Zysk, M., Yamaguchi, Y., & Schmitz, J. Ü. (2002) · Human Immunology · doi:10.1016/s0198-8859(02)00752-8 · Cited by 220
Toll-like receptor 9 signaling protects against murine lupus.
Wu, X.-B., & Peng, S. L. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21553 · Cited by 246
Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice
Santiago‐Raber, M., Dunand-Sauthier, I., Wu, T., Li, Q., Uematsu, S., Akira, S., Reith, W., Mohan, C., Kotzin, B. L., & Izui, S. (2009) · Journal of Autoimmunity · doi:10.1016/j.jaut.2009.11.001 · Cited by 225
Self-citation
Innate immune recognition of DNA: A recent history
Dempsey, A., & Bowie, A. (2015) · Virology · doi:10.1016/j.virol.2015.03.013 · Cited by 229
“The first PRR implicated in detection of DNA was TLR9 (Figure 1), shown in 2000 to be responsible for the ability of mice to respond to CpG DNA [9], leading to cytokine and IFNI induction via NF-κB and IRF7 respectively [2].”
Influential
Activation of Macrophages by Linear (1→3)-β-d-Glucans
Kataoka, K., Muta, T., Yamazaki, S., & Takeshige, K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206756200 · Cited by 219
Expression of Functional TLR4 Confers Proinflammatory Responsiveness to Trypanosoma cruzi Glycoinositolphospholipids and Higher Resistance to Infection with T. cruzi
Oliveira, A. C., Peixoto, J. R., de Arruda, L. B., Campos, M. A., Gazzinelli, R. T., Golenbock, D. T., Akira, S., Previato, J. O., Mendonça‐Previato, L., Nóbrega, A., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.9.5688 · Cited by 219
“A unique pathogen-associated molecular pattern (PAMP)4 ligand has been ascribed to date for some TLRs, such as flagellin for TLR5 (3) and CpG DNA for TLR9 (4).”
BackgroundSelf-citation
Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity
Gallo, P. M., Rapsinski, G. J., Wilson, R. P., Oppong, G. O., Sriram, U., Goulian, M., Buttaro, B. A., Caricchio, R., Gallucci, S., & Tükel, Ç. (2015) · Immunity · doi:10.1016/j.immuni.2015.06.002 · Cited by 228
“Although studies on eDNA and its sensors are limited, bacterial dsDNA can stimulate TLR9 (Hemmi et al., 2000) and cytosolic STING-dependent DNA sensors, resulting in a type I interferon response (Ishikawa et al., 2009).”
Influential
Mast Cells as Sensors of Cell Injury through IL-33 Recognition
Enoksson, M., Lyberg, K., Möller-Westerberg, C., Fallon, P. G., Nilsson, G. P., & Lunderius-Andersson, C. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003383 · Cited by 229
“To pinpoint the upstream receptor of MyD88 that responds to necrotic cell supernatant, BMMCs were derived from TLR12/2, TLR22/2, TLR42/2, TLR52/2, TLR62/2, TLR72/2, TLR82/2, and TLR92/2 mice.”
Master sensors of pathogenic RNA – RIG-I like receptors
Schlee, M. (2013) · Immunobiology · doi:10.1016/j.imbio.2013.06.007 · Cited by 216
“2004; Hemmi et al.”
Toll-like Receptor 7 Mitigates Lethal West Nile Encephalitis via Interleukin 23-Dependent Immune Cell Infiltration and Homing
Town, T., Bai, F., Wang, T., Kaplan, A. T., Qian, F., Montgomery, R. R., Anderson, J. F., Flavell, R. A., & Fikrig, E. (2009) · Immunity · doi:10.1016/j.immuni.2008.11.012 · Cited by 226
Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease
Lazarus, R. M., Vercelli, D., Palmer, L. J., Klimecki, W. J., Silverman, E. K., Richter, B. G., Riva, A., Ramoni, M. F., Martínez, F. D., Weiss, S. T., et al. (2002) · Immunological Reviews · doi:10.1034/j.1600-065x.2002.19002.x · Cited by 215
Combined Action of Nucleic Acid-Sensing Toll-like Receptors and TLR11/TLR12 Heterodimers Imparts Resistance to Toxoplasma gondii in Mice
Andrade, W. A., Souza, M. D. C., Ramos-Martı́nez, E., Nagpal, K., Dutra, M. S., Melo, M. B., Bartholomeu, D. C., Ghosh, S., Golenbock, D. T., & Gazzinelli, R. T. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2012.12.003 · Cited by 216
“NAS-TLRs are important cognate receptors for viruses, bacteria, and different protozoan parasites (Alexopoulou et al., 2001; Bartholomeu et al., 2008; Benson et al., 2009; Caetano et al., 2011; Heil et al., 2004; Hemmi et al., 2000; Parroche et al., 2007).”
Background
siRNA and isRNA: two edges of one sword
Schlee, M., Hornung, V., & Hartmann, G. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.06.001 · Cited by 217
“While TLR7 was found to sense single-stranded RNA [53,54], TLR9 detects so-called unmethylated CpG motifs in DNA [55].”
Background
Activation of Toll-like Receptor 5 on Breast Cancer Cells by Flagellin Suppresses Cell Proliferation and Tumor Growth
Cai, Z., Sanchez, A., Shi, Z., Zhang, T., Liu, M., & Zhang, D. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-1993 · Cited by 218
“org Cancer Res; 71(7) April 1, 2011 2467”
BackgroundInfluential
Resurrection of endogenous retroviruses in antibody-deficient mice
Young, G. R., Eksmond, U., Salcedo, R., Alexopoulou, L., Stoye, J. P., & Kassiotis, G. (2012) · Nature · doi:10.1038/nature11599 · Cited by 215
Plasmacytoid dendritic cell precursors/type I interferon-producing cells sense viral infection by Toll-like receptor (TLR) 7 and TLR9
Ito, T., Wang, Y., & Liu, Y.-J. (2004) · Springer Seminars in Immunopathology · doi:10.1007/s00281-004-0180-4 · Cited by 223
“bacterial and viral DNA [25, 26].”
The Art of the Probable: System Control in the Adaptive Immune System
Germain, R. N. (2001) · Science · doi:10.1126/science.1062946 · Cited by 215
Microparticles as vaccine adjuvants and delivery systems
O’Hagan, D. T., & Singh, M. (2003) · Expert Review of Vaccines · doi:10.1586/14760584.2.2.269 · Cited by 214
T Cell-Independent and Toll-like Receptor-Dependent Antigen-Driven Activation of Autoreactive B Cells
Herlands, R., Christensen, S. R., Sweet, R. A., Hershberg, U., & Shlomchik, M. J. (2008) · Immunity · doi:10.1016/j.immuni.2008.06.009 · Cited by 214
“Rather, we suggest that the partial dependence on TLR7 indicates that the autoAg recognized by PL2-3 in vivo has both DNA and RNA components.”
Influential
Chicken TLR21 Is an Innate CpG DNA Receptor Distinct from Mammalian TLR9
Keestra, A. M., de Zoete, M. R., Bouwman, L. I., & van Putten, J. P. M. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901921 · Cited by 217
“TLR9, which responds to unmethylated CpG DNA motifs (8, 9), is proteolytically cleaved in the endolysosomes, a process considered crucial for TLR9 activation (10–12).”
Background
Probiotics That Modify Disease Risk
Salminen, S., Gueimonde, M., & Isolauri, E. (2005) · Journal of Nutrition · doi:10.1093/jn/135.5.1294 · Cited by 220
“Probiotic effects may also be mediated via control of the balance between pro- and anti-inflammatory cytokines (1,15,25,29).”
DNA Sensing in the Innate Immune Response
Briard, B., Place, D. E., & Kanneganti, T. (2020) · Physiology · doi:10.1152/physiol.00022.2019 · Cited by 222
Probiotics, Prebiotics, and Synbiotics: Implications and Beneficial Effects against Irritable Bowel Syndrome
Simon, E., Călinoiu, L. F., Mitrea, L., & Vodnar, D. C. (2021) · Nutrients · doi:10.3390/nu13062112 · Cited by 235
TLR Engagement Prevents Transplantation Tolerance
Chen, L., Wang, T., Zhou, P., Ma, L., Yin, D., Shen, J., Molinero, L. L., Nozaki, T., Phillips, T. L., Uematsu, S., et al. (2006) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2006.01489.x · Cited by 213
“Thirty nanograms of each cDNA reaction was amplified in duplicate reactions using the Singleplex TaqMan Reaction Mix with primers (Assays on DemandTM) specific for CCL17/TARC, CCL22/MDC and L32 (Applied Biosystems, Foster City, CA).”
BackgroundInfluentialSelf-citation
The Role of Toll-like Receptors in the Pathogenesis and Treatment of Dermatological Disease
McInturff, J. E., Modlin, R. L., & Kim, J. (2005) · Journal of Investigative Dermatology · doi:10.1111/j.0022-202x.2004.23459.x · Cited by 213
“For instance, TLR9 mediates the response to unmethylated CpG DNA found in bacterial genomes, whereas TLR3 mediates the response to viral double-stranded RNA”
Background
Cytosolic DNA sensors regulating type I interferon induction
Keating, S. E., Baran, M., & Bowie, A. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.08.004 · Cited by 212
The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter
Hasan, U. A., Zannetti, C., Parroche, P., Goutagny, N., Malfroy, M., Roblot, G., Carreira, C., Hussain, I., Müller, M. B. D., Taylor‐Papadimitriou, J., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20122394 · Cited by 219
“TLR9 was one of the first innate immune receptors to be identified (Hemmi et al., 2000).”
Background
Non-viral COVID-19 vaccine delivery systems
Park, K. S., Sun, X., Aikins, M. E., & Moon, J. J. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.008 · Cited by 216
“Co-delivery of DNA plasmids and plasmids encoding cytokines, chemokines, or costimulatory molecules has had a positive effect on immune response [53,54].”
The emerging role of interferon in human systemic lupus erythematosus
Baechler, E. C., Gregersen, P. K., & Behrens, T. W. (2004) · Current Opinion in Immunology · doi:10.1016/j.coi.2004.09.014 · Cited by 212
TLR-Induced Inflammation in Cystic Fibrosis and Non-Cystic Fibrosis Airway Epithelial Cells
Greene, C. M., Carroll, T. P., Smith, S. G. J., Taggart, C. C., Devaney, J., Griffin, S., O'Neill, S. J., & McElvaney, N. G. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.3.1638 · Cited by 211
Vaccines that facilitate antigen entry into dendritic cells
Gamvrellis, A., Leong, D., Hanley, J. C., Xiang, S. D., Mottram, P. L., & Plebanski, M. (2004) · Immunology and Cell Biology · doi:10.1111/j.0818-9641.2004.01271.x · Cited by 216
TLR2: cellular sensor for microbial and endogenous molecular patterns.
Kirschning, C., & Schumann, R. (2002) · Current Topics in Microbiology and Immunology · doi:10.1007/978-3-642-59430-4_8 · Cited by 232
Interactions between bacterial CpG-DNA and TLR9 bridge innate and adaptive immunity
Wagner, H. (2002) · Current Opinion in Microbiology · doi:10.1016/s1369-5274(02)00287-4 · Cited by 215
Self-citation
Plasmodium berghei Infection in Mice Induces Liver Injury by an IL-12- and Toll-Like Receptor/Myeloid Differentiation Factor 88-Dependent Mechanism
Adachi, K., Tsutsui, H., Kashiwamura, S., Seki, E., Nakano, H., Takeuchi, O., Takeda, K., Okumura, K., Kaer, L. V., Okamura, H., et al. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.10.5928 · Cited by 214
“To date, nine different TLRs have been described (14, 15, 18).”
BackgroundSelf-citation
Role of Toll-Like Receptors in Changes in Gene Expression and NF-κB Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide
Liu, S., Gallo, D. J., Green, A. M., Williams, D. L., Gong, X., Shapiro, R. A., Gambotto, A. A., Humphris, E. L., Vodovotz, Y., & Billiar, T. R. (2002) · Infection and Immunity · doi:10.1128/iai.70.7.3433-3442.2002 · Cited by 246
“Hepatocytes expressed TLR1 through TLR9 as well as MyD88 and MD-2 transcripts, as shown by reverse transcriptase PCR analysis, indicating that hepatocytes express all known microbe recognition molecules.”
Background
Toll-like receptor 9 acts at an early stage in host defence against pneumococcal infection
Albiger, B., Dahlberg, S., Sandgren, A., Wartha, F., Beiter, K., Katsuragi, H., Akira, S., Normark, S. J., & Henriques‐Normark, B. (2006) · Cellular Microbiology · doi:10.1111/j.1462-5822.2006.00814.x · Cited by 210
“recognizes unmethylated CpG motifs (Hemmi et al., 2000).”
BackgroundInfluentialSelf-citation
Dietary synbiotic application modulates Atlantic salmon (Salmo salar) intestinal microbial communities and intestinal immunity
Abid, A. A. D. M., Davies, S. J., Waines, P., Emery, M., Castex, M., Gioacchini, G., Carnevali, O., Bickerdike, R., Romero, J., & Merrifield, D. L. (2013) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2013.09.039 · Cited by 210
“TLR3 is involved in the recognition of double-stranded RNA (dsRNA) or DNA containing unmethylated CpG motifs and it is specialized in viral detection [15,16].”
Background
Viral recognition by Toll-like receptors
Barton, G. M. (2007) · Seminars in Immunology · doi:10.1016/j.smim.2007.01.003 · Cited by 209
Dectin-1 Interaction with Mycobacterium tuberculosis Leads to Enhanced IL-12p40 Production by Splenic Dendritic Cells
Rothfuchs, A. G., Báfica, A. L. B., Feng, C. G., Egen, J. G., Williams, D. L., Brown, G. D., & Sher, A. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.3463 · Cited by 219
“CD11b / (24), TLR2 / (25), TLR9 / (26), MyD88 / (27), and IL10 / (28) mice were originally generated by homologous recombination in embryonic stem cells as previously described.”
Method
Toll-Like Receptors (TLRs) and Their Ligands
Uematsu, S., & Akira, S. (2007) · Handbook of experimental pharmacology · doi:10.1007/978-3-540-72167-3_1 · Cited by 215
“Besides TLR7 and TLR8, TLR3 and TLR9 are exclusively expressed in endosomal compartments not on cell surfaces (Latz et al., 2004).”
BackgroundInfluentialSelf-citation
Activation of Toll-Like Receptor 9 by DNA from Different Bacterial Species
Dalpke, A. H., Frank, J. K., Peter, M. E., & Heeg, K. M. (2006) · Infection and Immunity · doi:10.1128/iai.74.2.940-946.2006 · Cited by 205
“TLR-9 has been identified as the DNA-recognizing receptor (7).”
Background
Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells
Tartey, S., & Takeuchi, O. (2017) · International Reviews of Immunology · doi:10.1080/08830185.2016.1261318 · Cited by 209
“TLR9 was first cloned and identified as a receptor for unmethylated cytosine-phosphate-guanosine (CpG) DNA as well as for bacterial DNA [20].”
BackgroundSelf-citation
DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia
Lam, L., Murphy, S., Kokkinaki, D., Venosa, A., Sherrill-Mix, S. A., Casu, C., Rivella, S., Weiner, A. I., Park, J., Shin, S., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abj1008 · Cited by 221
Activation of toll‐like receptor‐9 induces progression of renal disease in MRL‐Fas(lpr) mice
Anders, H., Vielhauer, V., Eis, V., Linde, Y., Kretzler, M., de Lema, G. P., Strutz, F. M., Bauer, S., Rutz, M., Wagner, H., et al. (2004) · The FASEB Journal · doi:10.1096/fj.03-0646fje · Cited by 207
“TLR9, the CpG-DNA receptor, discriminates foreign from self-DNA by the state of methylation, asin contrast to bacterial DNAvertebrate DNA is usually methylated (3).”
BackgroundSelf-citation
Strategies for enhancing the immunostimulatory effects of CpG oligodeoxynucleotides
Mutwiri, G., Nichani, A., Babiuk, S., & Babiuk, L. A. (2004) · Journal of Controlled Release · doi:10.1016/j.jconrel.2004.02.022 · Cited by 207
Pathogenesis of sepsis: new concepts and implications for future treatment
Bochud, P., & Calandra, T. (2003) · BMJ · doi:10.1136/bmj.326.7383.262 · Cited by 208
Pathogenesis of prion diseases: current status and future outlook
Aguzzi, A., & Heikenwalder, M. (2006) · Nature Reviews Microbiology · doi:10.1038/nrmicro1492 · Cited by 207
“For example, unmethylated cytosine phosphate guanosine (CpG) motifs present in bacterial DNA can stimulate mouse and human immune responses through TLR9 (Ref”
Background
The inflammatory role of platelets via their TLRs and Siglec receptors
Cognasse, F. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00083 · Cited by 226
“The location of TLR9 is limited to the endosomes in eukaryotic cells, enabling it to recognize the internal constituents of pathogens, which are often released after they are endocytosed (89, 133).”
Background
Innate immunity against vaccinia virus is mediated by TLR2 and requires TLR-independent production of IFN-β
Zhu, J., Martinez, J., Huang, X., & Yang, Y. (2006) · Blood · doi:10.1182/blood-2006-06-027136 · Cited by 207
Virus Binding to a Plasma Membrane Receptor Triggers Interleukin-1α-Mediated Proinflammatory Macrophage Response In Vivo
Paolo, N. C. D., Miao, E. A., Iwakura, Y., Murali‐Krishna, K., Aderem, A. A., Flavell, R. A., Papayannopoulou, T., & Shayakhmetov, D. M. (2009) · Immunity · doi:10.1016/j.immuni.2009.04.015 · Cited by 206
“To define whether the early expression of proinflammaroty cytokines and chemokines depends on the signaling of these receptors, we injected Ad in Il1r1 / , Ifnar / , and Tlr9 / mice (Hemmi et al., 2000; Kolumam et al., 2005).”
Background
Outer membrane vesicle vaccines
Micoli, F., & MacLennan, C. A. (2020) · Seminars in Immunology · doi:10.1016/j.smim.2020.101433 · Cited by 215
Recent advances in veterinary vaccine adjuvants
Singh, M., & O’Hagan, D. T. (2003) · International Journal for Parasitology · doi:10.1016/s0020-7519(03)00053-5 · Cited by 207
MyD88-Dependent and -Independent Murine Cytomegalovirus Sensing for IFN-α Release and Initiation of Immune Responses In Vivo
Delale, T., Paquin, A., Asselin‐Paturel, C., Dalod, M., Brizard, G., Bates, E. E. M., Kastner, P., Chan, S. H., Akira, S., Vicari, A. P., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.10.6723 · Cited by 206
Self-citation
Role of the innate immune system in host defence against bacterial infections: focus on the Toll‐like receptors
Albiger, B., Dahlberg, S., Henriques‐Normark, B., & Normark, S. J. (2007) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2007.01821.x · Cited by 212
Toll-like receptors and their role in persistent pain
Lacagnina, M. J., Watkins, L. R., & Grace, P. M. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.006 · Cited by 216
“TLR9 is localized to the luminal surface of lysosomes and is activated by DNA with unmethylated CpG dinucleotides (Ahmad-Nejad et al., 2002; Hemmi et al., 2000).”
Coccidioidomycosis: host response and vaccine development
Cox, R. A., & Magee, D. M. (2004) · Clinical Microbiology Reviews · doi:10.1128/cmr.17.4.804-839.2004 · Cited by 205
“Recent studies have shown that unmethylated CpG triggers innate immunity through TLR9 (139).”
Background
The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system
Engel, A. L., Holt, G. E., & Lu, H. (2011) · Expert Review of Clinical Pharmacology · doi:10.1586/ecp.11.5 · Cited by 205
Essential roles of CD14 and lipopolysaccharide‐binding protein for activation of toll‐like receptor (TLR)2 as well as TLR4
Muta, T., & Takeshige, K. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02385.x · Cited by 205
Replication-Dependent Potent IFN-α Induction in Human Plasmacytoid Dendritic Cells by a Single-Stranded RNA Virus
Hornung, V., Schlender, J., Guenthner‐Biller, M., Rothenfußer, S., Endres, S., Conzelmann, K., & Hartmann, G. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.10.5935 · Cited by 204
“MyD88-independent IFN- induction by Sendai virus in PDC confirmed that ssRNA viruses indeed can be detected by PDC without the usage of endosomal TLR7, TLR8, and TLR9, because these TLRs depend on the adaptor molecule MyD88 (33, 34).”
BackgroundInfluential
A2A adenosine receptors and C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli
Csóka, B., Nemeth, Z. H., Virág, L., Gergely, P., Leibovich, S. J., Pacher, P., Sun, C.-X., Blackburn, M. R., Vizi, E. S., Deitch, E. A., et al. (2007) · Blood · doi:10.1182/blood-2007-01-065870 · Cited by 207
Proteasomal Degradation of Herpes Simplex Virus Capsids in Macrophages Releases DNA to the Cytosol for Recognition by DNA Sensors
Horan, K., Hansen, K., Jakobsen, M. R., Holm, C. K., Søby, S., Unterholzner, L., Thompson, M., West, J. A., Iversen, M. B., Rasmussen, S. B., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202749 · Cited by 212
“DNA represents a potent PAMP stimulating IFN responses in many cell types (12-14).”
Background
The Interactome of the Glucocorticoid Receptor and Its Influence on the Actions of Glucocorticoids in Combatting Inflammatory and Infectious Diseases
Πέττα, Ι., Dejager, L., Ballegeer, M., Lievens, S., Tavernier, J. H., Bosscher, K. D., & Libert, C. (2016) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00064-15 · Cited by 212
“TLR9 detects unmethylated CpG DNA in the genomes of viruses and bacteria (78).”
Background
Cytochrome c as a Potentially Clinical Useful Marker of Mitochondrial and Cellular Damage
Eleftheriadis, T., Pissas, G., Liakopoulos, V., & Stefanidis, I. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00279 · Cited by 205
Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case–control disease association studies☆☆This work was supported by Programs for Genomic Applications, Grant U01 HL66795, Innate Immunity in Heart, Lung and Blood Disease, from the National Heart, Lung and Blood Institute.
Lazarus, R. M., Klimecki, W. T., Raby, B. A., Vercelli, D., Palmer, L. J., Kwiatkowski, D. J., Silverman, E. K., Martinez, F., & Weiss, S. T. (2003) · Genomics · doi:10.1016/s0888-7543(02)00022-8 · Cited by 206
Myeloid heme oxygenase–1 regulates innate immunity and autoimmunity by modulating IFN-β production
Tzima, S., Victoratos, P., Kranidioti, K., Alexiou, M. V., & Kollias, G. A. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20081582 · Cited by 204
“The specific ligands recognized by IFN-/–inducing TLRs include dsRNA for TLR3 (1), LPS for TLR4 (2), ssRNA for TLR7 and 8 (3, 4), and unmethylated CpG-DNA for TLR9 (5).”
BackgroundMethodInfluential
Cutting Edge: Activation of Murine TLR8 by a Combination of Imidazoquinoline Immune Response Modifiers and PolyT Oligodeoxynucleotides
Gorden, K. B., Qiu, X., Binsfeld, C. C. A., Vasilakos, J. P., & Alkan, Ş. Ş. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.10.6584 · Cited by 204
Toll‐like receptors and their role in periodontal health and disease
Mahanonda, R., & Pichyangkul, S. (2007) · Periodontology 2000 · doi:10.1111/j.1600-0757.2006.00179.x · Cited by 208
Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway
Georgel, P., Jiang, Z., Kunz, S., Janssen, E. M., Mols, J., Hoebe, K. H. N., Bahram, S., Oldstone, M. B. A., & Beutler, B. (2007) · Virology · doi:10.1016/j.virol.2006.12.032 · Cited by 201
“Like TLRs 3, 7, 8, and 9, which sense nucleic acids (Alexopoulou et al., 2001; Heil et al., 2004; Hemmi et al., 2000; Lund et al., 2004) and are known to participate in defense against viral infections (Alexopoulou et al., 2001; Krug et al., 2004; Tabeta et al., 2004), TLR4 is capable of ⁎…”

Authors: Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., & Akira, S.
Affiliations: Research Institute for Microbial Diseases, The University of Osaka (JP)
Japan Science and Technology Agency (JP)
Technical University of Munich (DE)
Corresponding author: Akira, Shizuo
ORCID: Hemmi, Hiroaki
Takeuchi, Osamu
Kawai, Taro
Kaisho, Tsuneyasu
Sato, Shintaro
Sanjo, Hideki
Hoshino, Katsuaki
Takeda, Kiyoshi
Akira, Shizuo
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2000-12-07
Volume: 408
Issue: 6813
Pages: 740-745
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35047123
OpenAlex: W1514540900
Cited by: 6,491
References: 33
Citations by year: 2026: 85 · 2025: 115 · 2024: 136 · 2023: 167 · 2022: 156 · 2021: 191 · 2020: 180 · 2019: 164 · 2018: 187 · 2017: 219 · 2016: 201 · 2015: 226 · 2014: 276 · 2013: 281 · 2012: 235
FWCI: 102.08
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Japan Society for the Promotion of Science
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: TLR9, CpG, innate immunity, T helper 1 response, adjuvants, vaccination, dendritic cell maturation, macrophage cytokine production, self-DNA, TLR9-deficient mice
MeSH terms: Amino Acid Sequence, Animals, Antigens, Differentiation, Base Sequence, Cells, Cultured, Cloning, Molecular, Dendritic Cells, DNA-Binding Proteins, DNA, Bacterial, T-Lymphocytes, Helper-Inducer, Humans, Membrane Glycoproteins, Mice, Inbred C57BL, Molecular Sequence Data, Receptors, Cell Surface, Receptors, Immunologic, Dinucleoside Phosphates, Signal Transduction, Cytokines, Mutagenesis, Sequence Homology, Amino Acid, Drosophila Proteins, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Toll-Like Receptor 9, Mice, Myeloid Differentiation Factor 88

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

A Toll-like receptor recognizes bacterial DNA

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks