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
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.
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“all of the AAV-induced cytokines and chemokines can be upregulated by activation of TLR9 in the periphery using synthetic CpG-rich oligonucleotides.8,9,10,11,12,52,53,54,55,56,57,58”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [52]
Citations
Cites
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
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-citationCpG 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
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-citationInnate 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-citationA 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
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Items 1,001–1,045 of 1,045
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Tolle, L. B., & Standiford, T. J. (2013) · The Journal of Pathology · doi:10.1002/path.4124 · Cited by 157
Expression of Toll-Like Receptors in the Developing Brain
Kaul, D., Habbel, P., Derkow, K., Krüger, C., Franzoni, E., Wulczyn, F. G., Bereswill, S., Nitsch, R., Schott, E., Veh, R., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037767 · Cited by 141
“Although their brains have not been investigated in detail on a microanatomic level, no major impairment in CNS development resulting in morphogenetic failures in these animals was described [28,29].”
BackgroundMitochondrial damage-associated molecular patterns and vascular function
Wenceslau, C. F., McCarthy, C. G., Szasz, T., Spitler, K., Goulopoulou, S., Webb, R. C., & Working Group on DAMPs in Cardiovascular Disease (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu047 · Cited by 135
“Bacterial DNA is recognized by the TLR9, a member of the highly conserved PRRs known as TLRs.(26) Containing the inflammatogenic unmethylated CpG DNA motifs, mtDNA also acts as a ligand for TLR9.”
BackgroundTargeting the TLR9–MyD88 pathway in the regulation of adaptive immune responses
Huang, X., & Yang, Y. (2010) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2010.501333 · Cited by 121
“1 TLR9 recognition of CpG DNA TLR9 recognizes synthetic CpG-motif-containing oligodeoxynucleotides (ODN) [7,19].”
BackgroundInfluentialCpG oligodeoxynucleotides as immunotherapy in cancer
Jahrsdörfer, B., & Weiner, G. J. (2008) · Update on Cancer Therapeutics · doi:10.1016/j.uct.2007.11.003 · Cited by 132
Kwissa, M., Nakaya, H. I., Oluoch, H., & Pulendran, B. (2012) · Blood · doi:10.1182/blood-2011-10-388579 · Cited by 132
Toll‐like receptors and pregnancy: Trophoblast as modulators of the immune response
Koga, K., Aldo, P. B., & Mor, G. (2009) · Journal of Obstetrics and Gynaecology Research · doi:10.1111/j.1447-0756.2008.00963.x · Cited by 130
Yasuda, K., Richez, C., Uccellini, M. B., Richards, R. J., Bonegio, R. G., Akira, S., Monestier, M., Corley, R. B., Viglianti, G. A., Marshak-Rothstein, A., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900399 · Cited by 118
“These were (1) the 607-bp CG50 fragment that contains 50 optimal CpG motifs; (2) a 726-bp fragment derived from the promoter region of HIV-1 that contains 27 unmethylated CpG dinucleotides but no optimal CpG motifs (referred to as CGSubOp); and (3) a 629-bp fragment derived from the HIV-1 gag gene that contains no CpG…”
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Arimoto, K.-I., Miyauchi, S., Stoner, S. A., Fan, J.-B., & Zhang, D.-E. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.2mir0817-342r · Cited by 117
Kaminski, J. J., Schattgen, S. A., Tzeng, T.-C., Bode, C., Klinman, D. M., & Fitzgerald, K. A. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300530 · Cited by 112
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Nucleic acid‐sensing TLR s and autoimmunity: novel insights from structural and cell biology
Pelka, K., Shibata, T., Miyake, K., & Latz, E. (2016) · Immunological Reviews · doi:10.1111/imr.12375 · Cited by 110
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BackgroundRegulation of autoreactive B cell responses to endogenous TLR ligands
Avalos, A. M., Busconi, L., & Marshak-Rothstein, A. (2010) · Autoimmunity · doi:10.3109/08916930903374618 · Cited by 114
“TLR9 was originally identified as a receptor for bacterial DNA, which preferentially bound the hypomethylated CpG motifs found in prokaryotic but not eukaryotic DNA [7].”
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Dalpke, A. H., & Helm, M. (2012) · RNA Biology · doi:10.4161/rna.20206 · Cited by 113
Cytoplasmic Mechanisms of Recognition and Defense of Microbial Nucleic Acids
Hu, M.-M., & Shu, H.-B. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100617-062903 · Cited by 110
A tale of two sites: how inflammation can reshape the microbiomes of the gut and lungs
Scales, B. S., Dickson, R. P., & Huffnagle, G. B. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.3mr0316-106r · Cited by 109
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BackgroundQin, J., Jiang, Z., Qian, Y., Casanova, J.-L., & Li, X. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400785200 · Cited by 110
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Zhu, S., Ashok, M., Li, J., Li, W., Yang, H., Wang, P., Tracey, K. J., Sama, A. E., & Wang, H. (2009) · Molecular Medicine · doi:10.2119/molmed.2009.00062 · Cited by 109
“Innate immune cells (such as macrophages) are equipped with pattern recognition receptors (such as Toll-like receptors [TLRs] 2, 4, and 9) (1–3), which specifically recognize pathogen- or damage-associated molecular patterns (PAMPs or DAMPs) (3,4).”
Calcineurin Negatively Regulates TLR-Mediated Activation Pathways
Kang, Y. J., Kusler, B., Otsuka, M., Hughes, M., Suzuki, N., Suzuki, S., Yeh, W.-C., Akira, S., Han, J., & Jones, P. P. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.7.4598 · Cited by 104
“Mice, cell culture, and transfections Thioglycolate-elicited peritoneal macrophages from wild-type mice, mice deficient in MyD88, TRIF, TLR2, TLR3, or TLR4, or from TLR9 mutant TLR9CpG1/CpG1 mice (provided to J. Han by B. Beutler, The Scripps Research Institute, La Jolla, CA) were aseptically harvested.”
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Maatouk, L., Compagnion, A.-C., Sauvage, M.-A. C.-D., Bemelmans, A.-P., Leclere-Turbant, S., Cirotteau, V., Tohme, M., Beke, A., Trichet, M., Bazin, V., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04569-y · Cited by 95
Diner, B. A., Lum, K. K., Javitt, A., & Cristea, I. M. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m114.047068 · Cited by 93
Damiano, V., Caputo, R., Bianco, R., D'Armiento, F. P., Leonardi, A., De Placido, S., Bianco, A. R., Agrawal, S., Ciardiello, F., & Tortora, G. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1943 · Cited by 90
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BackgroundHayashi, K., Taura, M., & Iwasaki, A. (2018) · Science Signaling · doi:10.1126/scisignal.aan4144 · Cited by 76
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Shi, P., Grobe, J. L., Desland, F. A., Zhou, G., Shen, X. Z., Shan, Z., Liu, M., Raizada, M. K., & Sumners, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092937 · Cited by 75
“However, it primes the cells to produce a much stronger effects to a second stimulation, such as elicited by LPS, Cytosine-phosphateguanosine (CpG) and TNFa [28–30].”
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Boutajangout, A., & Wisniewski, T. (2013) · International Journal of Cell Biology · doi:10.1155/2013/576383 · Cited by 69
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Gómez, J. M. M., Fischer, S., Csaba, N., Kündig, T. M., Merkle, H. P., Gander, B., & Johansen, P. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9318-0 · Cited by 63
Abuaita, B. H., Burkholder, K. M., Boles, B. R., & O’Riordan, M. X. (2015) · mBio · doi:10.1128/mbio.00705-15 · Cited by 48
“individual TLR knockout mouse strains on a C57BL/6 background (50, 51).”
Chandler, L., Yusuf, I., McClements, M., Barnard, A., MacLaren, R., & Xue, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144972 · Cited by 49
“, 60–90% of mammalian CpGs are methylated) [23,24].”
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“Activation of toll-like receptors (TLRs) that recognize distinct pathogen-associated molecular patterns unique to bacteria, viruses, fungi, parasites, and some endogenous ligands1 is well recognized as an initiation step in the inflammatory cascade that follows corneal infection.2–5 Scarring and opacification of the c…”
BackgroundSakurai, H., Sakurai, F., Kawabata, K., Sasaki, T., Koizumi, N., Huang, H., Tashiro, K., Kurachi, S., Nakagawa, S., & Mizuguchi, H. (2007) · Journal of Controlled Release · doi:10.1016/j.jconrel.2006.11.030 · Cited by 40
MyD88-dependent changes in the pulmonary transcriptome after infection with Chlamydia pneumoniae
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Butterfield, J. S. S., Biswas, M., Shirley, J. L., Kumar, S. R. P., Sherman, A., Terhorst, C., Ling, C., & Herzog, R. W. (2019) · Human Gene Therapy Methods · doi:10.1089/hgtb.2019.013 · Cited by 35
van Tongeren, J., Röschmann, K. I. L., Reinartz, S. M., Luiten, S., Fokkens, W. J., de Jong, E. C., & van Drunen, C. M. (2015) · Clinical and Translational Allergy · doi:10.1186/s13601-015-0086-3 · Cited by 30
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Self-citationSuriano, C. M., Kumar, N., Verpeut, J. L., Ma, J., Jung, C., Dunn, C. E., Carvajal, B. V., Nguyen, A. V., & Boulanger, L. M. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.036 · Cited by 21
“8 – 12,52 – 58”
Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3)
(2002) · doi:10.1002/1521-4141(200208)32:8
Self-citation
Metadata
- 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
- Venue
- Nature
- Published
- 2000-12-07
- Volume
- 408
- Issue
- 6813
- Pages
- 740-745
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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
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