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

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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

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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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Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene
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Self-citation
CpG motifs in bacterial DNA trigger direct B-cell activation
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Self-citation
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Background
Synergistic Activation of Innate Immunity by Double-Stranded RNA and CpG DNA Promotes Enhanced Antitumor Activity
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BackgroundInfluential
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Background
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Matsumoto, M., Oshiumi, H., & Seya, T. (2011) · Reviews in Medical Virology · doi:10.1002/rmv.680 · Cited by 186
Self-citation
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Background
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BackgroundInfluentialSelf-citation
cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells
Paijo, J., Döring, M., Spanier, J., Grabski, E., Nooruzzaman, M., Schmidt, T., Witte, G., Messerle, M., Hornung, V., Kaever, V., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005546 · Cited by 194
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BackgroundInfluential
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Background
Toll Meets Bacterial CpG-DNA
Wagner, H. (2001) · Immunity · doi:10.1016/s1074-7613(01)00144-3 · Cited by 181
Self-citation
Systemic Lupus Erythematosus: Multiple Immunological Phenotypes in a Complex Genetic Disease
Fairhurst, A., Wandstrat, A. E., & Wakeland, E. K. (2006) · Advances in immunology · doi:10.1016/s0065-2776(06)92001-x · Cited by 180
“TLR9 was first described as a receptor essential for recognition of bacterial DNA containing unmethylated CpG dinucleotides (Hemmi et al., 2000).”
Background
Aspergillus fumigatus antigens activate innate immune cells via toll‐like receptors 2 and 4
Braedel-Ruoff, S., Radsak, M. P., Einsele, H., Latgé, J., Michan, A., Loeffler, J., Haddad, Z., Grigoleit, U., Schild, H., & Hebart, H. F. (2004) · British Journal of Haematology · doi:10.1111/j.1365-2141.2004.04922.x · Cited by 180
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Melief, C. J. M. (2003) · European Journal of Immunology · doi:10.1002/eji.200324341 · Cited by 184
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Akira, S., & Takeda, K. (2004) · Comptes Rendus Biologies · doi:10.1016/j.crvi.2004.04.002 · Cited by 195
“conclusion [28].”
Self-citation
Predominant Role of Toll-Like Receptor 2 Versus 4 in Chlamydia pneumoniae -Induced Activation of Dendritic Cells
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“Pathogen-derived pattern ligands like endotoxin and CpG DNA stimulate dendritic cells to increase the expression of MHC class II, CD40, CD80, and CD86 and to secrete cytokines like TNF- or IL-12p40 (20).”
BackgroundInfluentialSelf-citation
Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins
Kim, T. W., Hung, C., Ling, M. F., Juang, J., He, L., Hardwick, J. M., Kumar, S., & Wu, T. ‐. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17293 · Cited by 179
“as cytosine linked to a guanine by a phosphate bond (CpG) islands (30), which have been shown to cause simultaneous maturation and activation of murine DCs (31) and alter the expression of cytokines such as IL-12 and IFN-γ (30, 32).”
BackgroundInfluential
Locked Nucleic Acid: A Potent Nucleic Acid Analog in Therapeutics and Biotechnology
Stenvang, J., Sørensen, M. D., & Wengel, J. (2004) · Oligonucleotides · doi:10.1089/1545457041526317 · Cited by 184
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Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model
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OMV Vaccines and the Role of TLR Agonists in Immune Response
Mancini, F., Rossi, O., Necchi, F., & Micoli, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124416 · Cited by 178
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Background
Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells
Megjugorac, N. J., Young, H. A., Amrute, S. B., Olshalsky, S. L., & Fitzgerald-Bocarsly, P. A. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0603291 · Cited by 178
“PDC also express TLR9, which contributes to nonspecific bacterial recognition through binding of bacterial CpG motifs [59].”
Background
Impaired Production of Proinflammatory Cytokines and Host Resistance to Acute Infection with Trypanosoma cruzi in Mice Lacking Functional Myeloid Differentiation Factor 88
Campos, M. A., Closel, M., Valente, E. P., Cardoso, J. E., Akira, S., Alvarez-Leite, J. I., Ropert, C., & Gazzinelli, R. T. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.3.1711 · Cited by 177
“cruzi genomic DNA has been demonstrated to be stimulatory for macrophages, DCs, and B lymphocytes, possibly via TLR-9 (26, 27).”
BackgroundInfluentialSelf-citation
Enhancement of immune responses by co-delivery of a CpG oligodeoxynucleotide and tetanus toxoid in biodegradable nanospheres
Diwan, M. (2002) · Journal of Controlled Release · doi:10.1016/s0168-3659(02)00275-4 · Cited by 177
Pathogen Recognition Receptors: Ligands and Signaling Pathways by Toll-Like Receptors
Sasai, M., & Yamamoto, M. (2013) · International Reviews of Immunology · doi:10.3109/08830185.2013.774391 · Cited by 185
“In contrast, TLR9 recognizes unmethylated CpG DNA, which is abundantly present in bacteria, viruses and parasites, but is not frequent in mammalian cells [50].”
Background
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Demento, S. L., Siefert, A. L., Bandyopadhyay, A., Sharp, F. A., & Fahmy, T. M. (2011) · Trends in biotechnology · doi:10.1016/j.tibtech.2011.02.004 · Cited by 177
The Expression and Functions of Toll-Like Receptors in Atherosclerosis
Cole, J. E., Georgiou, E. X., & Monaco, C. G. (2010) · Mediators of Inflammation · doi:10.1155/2010/393946 · Cited by 180
“TLR9 Hypomethylated CpG motifs in microbial DNA [241, 246, 247],”
Background
Toll-like receptor 3 is an essential component of the innate stress response in virus-induced cardiac injury
Harðarson, H. S., Baker, J. S., Zhao, Y., Purevjav, E., Huang, C., Alexopoulou, L., Li, N., Flavell, R. A., Bowles, N. E., & Vallejo, J. G. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00398.2006 · Cited by 177
“Briefly, to generate TLR3 / mice, we isolated the genomic DNA of the Tlr3 gene from a 129SV mouse genomic library.”
Background
Immunité naturelle
Delneste, Y., Beauvillain, C., & Jeannin, P. (2007) · médecine/sciences · doi:10.1051/medsci/200723167 · Cited by 177
Cellular processing and destinies of artificial DNA nanostructures
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Matsuda, N., & Hattori, Y. (2006) · Journal of Pharmacological Sciences · doi:10.1254/jphs.crj06010x · Cited by 174
Glucocorticoids and Tumor Necrosis Factor Alpha Cooperatively Regulate Toll-Like Receptor 2 Gene Expression
Hermoso, M. A., Matsuguchi, T., Smoak, K. A., & Cidlowski, J. A. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.11.4743-4756.2004 · Cited by 180
“To date, 10 distinct receptors have been reported which belong to the TLR family (5, 13, 23, 27, 35).”
Background
The physiological regulation of toll‐like receptor expression and function in humans
Lancaster, G. I., Khan, Q., Drysdale, P., Wallace, F., Jeukendrup, A. E., Drayson, M. T., & Gleeson, M. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2004.081224 · Cited by 176
“2001) and the production of inflammatory cytokines (Medzhitov et al. 1997; Hemmi et al. 2000; Alexopoulou et al. 2001; Hayashi et al. 2001; Yamamoto et al. 2002).”
BackgroundInfluential
Cutting Edge: Plasmacytoid Dendritic Cells Provide Innate Immune Protection against Mucosal Viral Infection In Situ
Lund, J. M., Linehan, M. M., Iijima, N., & Iwasaki, A. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.7510 · Cited by 176
“Female B6129PF2/J (wild type (WT); The Jackson Laboratory) and Tlr9 (F2 generations of mixed 129P2/OlaHsd, 129X1/SvJ, and C57BL/6 background) (27) mice were bred in the Yale animal facility.”
Background
An association study of asthma and total serum immunoglobin E levels for Toll‐like receptor polymorphisms in a Japanese population
Noguchi, E., Nishimura, F., Fukai, H., Kim, J. K., Ichikawa, K., Shibasaki, M., & Arinami, T. (2004) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.2004.01839.x · Cited by 176
Live Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis activate the inflammatory response through Toll-like receptors 2, 4, and 9 in species-specific patterns
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“2, G and H), a receptor previously associated with bacterial-unmethylated DNA [11].”
Background
Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus
Herbst, S., Shah, A., Mazón, M. J., Marzola, V., Jensen, B., Reed, A. K., Birrell, M. A., Saijo, S., Mostowy, S., Shaunak, S., et al. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404556 · Cited by 172
“C57BL/6 WT male mice (18–22 g; Harlan Ortech, UK), Rag / mice (Mombaerts et al, 1992), Dectin-1 / mice (Saijo et al, 2007), MyD88 / (Eltom et al, 2014) and TLR9 / mice (Hemmi et al, 2000) on a C57BL/6 background were housed in individually vented cages with free access to autoclaved food and water.”
Method
The cytoplasmic 'linker region' in Toll-like receptor 3 controls receptor localization and signaling
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“On the other hand, TLR9, known to be a receptor for bacterial CpG-DNA ( 37 ), localizes to the lysosomal compartment where CpG-induced signaling starts (38).”
Background
The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis
Roshan, M. H. K., Tambo, A., & Pace, N. P. (2016) · International Journal of Inflammation · doi:10.1155/2016/1532832 · Cited by 181
“While TLR2 and TLR4 are expressed on the cell surface, TLR9 colocalises to the endoplasmic reticulum in various cell types, including B-cells, macrophages, dendritic cells, and plasma cells [107].”
Background
Pattern recognition receptors in zebrafish provide functional and evolutionary insight into innate immune signaling pathways
Li, Y., Li, Y., Cao, X., Jin, X., & Jin, T. (2016) · Cellular and Molecular Immunology · doi:10.1038/cmi.2016.50 · Cited by 177
Lactobacilluscasei reduces CD8+ T cell‐mediated skin inflammation
Chapat, L., Chemin, K., Dubois, B., Bourdet‐Sicard, R., & Kaiserlian, D. (2004) · European Journal of Immunology · doi:10.1002/eji.200425139 · Cited by 175
Bacterial Fimbriae and Their Peptides Activate Human Gingival Epithelial Cells through Toll-Like Receptor 2
Asai, Y., Ohyama, Y., Gen, K., & Ogawa, T. (2001) · Infection and Immunity · doi:10.1128/iai.69.12.7387-7395.2001 · Cited by 175
“The relative expression levels were calculated as the density of the product of the respective target genes divided by that of -actin from the same cDNA.”
BackgroundInfluential
NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs
Schleicher, U., Liese, J., Knippertz, I., Kurzmann, C., Hesse, A., Heit, A., Fischer, J. A. A., Weiß, S., Kalinke, U., Kunz, S., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061293 · Cited by 174
“IFNAR−/− (66), IFN-β−/− (67), MyD88−/− (68), and TLR9−/− mice (69) were backcrossed to C57BL/6 mice for 10, 13, 8, or 10”
Putative association of a TLR9 promoter polymorphism with atopic eczema
Novak, N., Yu, C., Bußmann, C., Maintz, L., Peng, W., Hart, J., Hagemann, T., Diaz-Lacava, A. N., Baurecht, H., Klopp, N., et al. (2007) · Allergy · doi:10.1111/j.1398-9995.2007.01358.x · Cited by 174
“Potential-binding sites for transcription factors were identified on forward and backward strands of genomic DNA using the matinspector programme (release 7.0; Genomatix, Munich, Germany).”
BackgroundInfluential
The Molecular Basis for the Lack of Immunostimulatory Activity of Vertebrate DNA
Stacey, K. J., Young, G. R., Clark, F., Sester, D. P., Roberts, T. L., Naik, S. H., Sweet, M. J., & Hume, D. A. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3614 · Cited by 177
“Subsequent signaling requires a member of the Toll-like receptor (TLR)(3) family, TLR-9 (2).”
Background
The extracellular matrix protein mindin is a pattern-recognition molecule for microbial pathogens
He, Y.-W., Li, H., Zhang, J., Hsu, C.-L., Lin, E., Zhang, N., Guo, J., Forbush, K. A., & Bevan, M. J. (2004) · Nature Immunology · doi:10.1038/ni1021 · Cited by 171
The host response to naturally-derived extracellular matrix biomaterials
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RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon–γ‐primed macrophages
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Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release
Ilyinskii, P. O., Roy, C. J., O’Neil, C. P., Browning, E., Pittet, L. A., Altreuter, D. H., Alexis, F., Tonti, E., Shi, J., Basto, P. A., et al. (2014) · Vaccine · doi:10.1016/j.vaccine.2014.02.027 · Cited by 174
Sepsis and evolution of the innate immune response
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“Subsequently, TLR9 was shown to be required for responses to unmethylated CpG dinucleotides (19).”
Background
Contribution of Toll‐like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration†
Seki, E., Tsutsui, H., Iimuro, Y., Naka, T., Son, G., Akira, S., Kishimoto, T., Nakanishi, K., & Fujimoto, J. (2005) · Hepatology · doi:10.1002/hep.20603 · Cited by 176
Self-citation
MicroRNAs: Novel Regulators During the Immune Response
Bi, Y., Liu, G., & Yang, R. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21639 · Cited by 172
“…were stimulated with LPS, which signals through TLR4 (Medzhitov et al., 1997; Poltorak et al., 1998); hypomethylated DNA (CpG), a TLR9 ligand (Hemmi et al., 2000); or Pam3CSK4, a synthetic lipoprotein that activates TLR2 (Brightbill et al., 1999), and all four TLR ligands (including TLR3)…”
Method
TRIM11 Suppresses AIM2 Inflammasome by Degrading AIM2 via p62-Dependent Selective Autophagy
Liu, T., Tang, Q., Liu, K., Xie, W., Liu, X., Wang, H., Wang, R., & Cui, J. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.019 · Cited by 176
Early IL-2 Production by Mouse Dendritic Cells Is the Result of Microbial-Induced Priming
Granucci, F., Feau, S., Angéli, V., Trottein, F., & Ricciardi‐Castagnoli, P. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.10.5075 · Cited by 172
“To investigate the stimuli that could induce IL-2 production, mouse DCs were stimulated in vitro with LPS, a component of Gramnegative bacteria that signals through TLR4 (15), oligo DNA containing the unmethylated CpG motif of bacterial DNA that is recognized by TLR9 (16), zymosan (yeast cell wall particles), LTA (a c…”
Method
Lipoprotein is a predominant Toll-like receptor 2 ligand in Staphylococcus aureus cell wall components
Hashimoto, M., Tawaratsumida, K., Kariya, H., Aoyama, K., Tamura, T., & Suda, Y. (2005) · International Immunology · doi:10.1093/intimm/dxh374 · Cited by 171
“TLR4, the most characterized member of the family, in combination with an adapter molecule MD-2 has been shown to recognize LPS, an outer membrane component of gram-negative bacteria (2, 3). TLR9 has been reported to be involved in immune responses to unmethylated CpG DNA ( 4 ), and TLR3 and TLR7/8 sense viral double-…”
Background
B Cell–Intrinsic TLR7 Signaling Is Essential for the Development of Spontaneous Germinal Centers
Soni, C., Wong, E. B., Domeier, P. P., Khan, T. N., Satoh, T., Akira, S., & Rahman, Z. S. M. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401720 · Cited by 171
“TLR7-KO (34) and TLR9-KO (35) mice backcrossed to B6 mice for 10 generations were bred in-house.”
BackgroundSelf-citation
Role of CD4 T Cell Help and Costimulation in CD8 T Cell Responses During Listeria monocytogenes Infection
Shedlock, D. J., Whitmire, J. K., Tan, J. T., MacDonald, A. S., Ahmed, R., & Shen, H. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.4.2053 · Cited by 171
Vaccination with Heat-killed Leishmania Antigen or Recombinant Leishmanial Protein and CpG Oligodeoxynucleotides Induces Long-Term Memory CD4+and CD8+T Cell Responses and Protection Against Leishmania major Infection
Rhee, E. G., Méndez, S., Shah, J. A., Wu, C. Y., Kirman, J. R., Turon, T. N., Davey, D. F., Davis, H. L., Klinman, D. M., Coler, R. N., et al. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020147 · Cited by 171
“At the APC level, CpG ODN through toll-like receptor 9, augments both the activation and maturation of DC as well as the induction of proinflammatory cytokines (35).”
Background
EBV-Induced Gene 3 Transcription Is Induced by TLR Signaling in Primary Dendritic Cells via NF-κB Activation
Wirtz, S. J., Becker, C., Fantini, M. C., Nieuwenhuis, E. E. S., Tubbe, I., Galle, P. R., Schild, H., Birkenbach, M. P., Blumberg, R. S., & Neurath, M. F. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.5.2814 · Cited by 170
Hepatic DNA deposition drives drug‐induced liver injury and inflammation in mice
Marques, P. E., de Oliveira, A. G., Pereira, R. V. S., David, B. A., Gomides, L. F., Saraiva, A. M., Pires, D. A., Novaes, J. T., Patricio, D. D. O., Cisalpino, D., et al. (2014) · Hepatology · doi:10.1002/hep.27216 · Cited by 170
“DNA sensors include the endocytic receptor TLR9 (Toll-like receptor 9) (13, 14) and more recently discovered cytosolic, STING-dependent receptors such as c-GAS (15), DNA-PK (16), IFI16 (17), DAI (18)”
Background
TLR agonists as vaccine adjuvants: comparison of CpG ODN and Resiquimod (R-848)
Weeratna, R. D., Makinen, S. R., McCluskie, M. J., & Davis, H. L. (2005) · Vaccine · doi:10.1016/j.vaccine.2005.06.024 · Cited by 173
Innate immunity and adjuvants
Akira, S. (2011) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2011.0106 · Cited by 177
Self-citation
Evasion of the Immune Response by Trypanosoma cruzi during Acute Infection
Cardoso, M. S., Reis-Cunha, J. L., & Bartholomeu, D. C. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00659 · Cited by 170
Systemic application of CpG‐rich DNA suppresses adaptive T cell immunity via induction of IDO
Wingender, G., Garbi, N., Schumak, B., Jüngerkes, F., Endl, E., von Bubnoff, D., Steitz, J., Striegler, J., Moldenhauer, G., Tüting, T., et al. (2005) · European Journal of Immunology · doi:10.1002/eji.200535602 · Cited by 170
Self-citation
Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious diseases
Skevaki, C. L., Pararas, M. V., Kostelidou, K., Tsakris, A., & Routsias, J. G. (2015) · Clinical & Experimental Immunology · doi:10.1111/cei.12578 · Cited by 174
“Finally, TLR9 recognizes DNA from Herpes Simplex Virus 1/2 and unmethylated CpG motifs from bacteria and viruses [24-26].”
Background
Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases
Boyapati, R. K., Tamborska, A., Dorward, D. A., & Ho, G. (2017) · F1000Research · doi:10.12688/f1000research.10397.1 · Cited by 170
Innate immune receptors in platelets and platelet-leukocyte interactions
Dib, P. R. B., Quirino-Teixeira, A. C., Merij, L. B., Pinheiro, M. B. M., Rozini, S. V., Andrade, F. B., & Hottz, E. D. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.4mr0620-701r · Cited by 174
A Review of Inflammatory Bowel Disease: A Model of Microbial, Immune and Neuropsychological Integration
Tavakoli, P., Vollmer-Conna, U. S., Hadzi-Pavlovic, D., & Grimm, M. (2021) · Public health reviews · doi:10.3389/phrs.2021.1603990 · Cited by 173
“These receptors are sensitive to pathogen associatedmolecular patterns (PAMPs) such as bacterial lipopolysaccharides (LPS) [98], Gram-positive and mycobacterial lipopeptide [99], lipoteichoic acid (LTA) and peptidoglycan (PGN) [100], double stranded viral RNA and bacterial DNA [101], and reactive oxygen species (ROS)…”
Background
The Essential Role of Single Ig IL-1 Receptor-Related Molecule/Toll IL-1R8 in Regulation of Th2 Immune Response
Bulek, K., Swaidani, S., Qin, J., Lu, Y., Gulen, M. F., Herjan, T., Min, B., Kastelein, R. A., Aronica, M. A., Kosz‐Vnenchak, M., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0802729 · Cited by 178
Mitochondrial DNA in the regulation of innate immune responses
Fang, C., Wei, X., & Wei, Y. (2015) · Protein & Cell · doi:10.1007/s13238-015-0222-9 · Cited by 174
“Bacterial DNA is recognized by TLR9, a member of the highly conserved PRRs known as TLRs (Hemmi et al., 2000).”
Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns
Wit, D. D., Olislagers, V., Goriely, S., Vermeulen, F., Wagner, H., Goldman, M., & Willems, F. (2003) · Blood · doi:10.1182/blood-2003-04-1216 · Cited by 168
Self-citation
Toll-Like Receptor 9: A New Target of Ischemic Preconditioning in the Brain
Stevens, S. L., Ciesielski, T., Marsh, B. J., Yang, T., Homen, D. S., Boule, J.-L., Lessov, N. S., Simon, R. P., & Stenzel‐Poore, M. P. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600606 · Cited by 168
“Thus far, the known ligands for TLR9 include bacterial DNA containing unmethylated CpG motifs, certain double-stranded DNA viruses, and synthetic CpG ODNs such as CpG ODN 1826 used in the studies described here (Bauer et al, 2001; Hemmi et al, 2000; Krug et al, 2004).”
Background
Cellular and Humoral Mechanisms Involved in the Control of Tuberculosis
Zúñiga, J., Torres‐García, D., Santos-Mendoza, T., Rodrı́guez-Reyna, T. S., Granados, J., & Yunis, E. J. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/193923 · Cited by 176
“TLR9-deficient mice [37, 38, 51].”
Nuclear Membrane Rupture and Its Consequences
Maciejowski, J., & Hatch, E. M. (2020) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-020520-120627 · Cited by 170
“Nuclear membrane protection is understood to enable self-DNA to evade detection via physical separation from sensor proteins, which are primarily located in the cytoplasm (Hemmi et al. 2000, Hornung et al. 2009, Sun et al. 2013).”
Background
Evolution of effectors and receptors of innate immunity
Magor, B. G., & Magor, K. E. (2001) · Developmental & Comparative Immunology · doi:10.1016/s0145-305x(01)00029-5 · Cited by 166
DNA vaccines: developing new strategies to enhance immune responses
Abdulhaqq, S. A., & Weiner, D. B. (2008) · Immunologic Research · doi:10.1007/s12026-008-8076-3 · Cited by 167
“CpGs are recognized by Toll-like receptor 9 (TLR9), a receptor found on APCs [23].”
Background
The endless race betweenTrypanosoma cruziand host immunity: lessons for and beyond Chagas disease
Junqueira, C., Caetano, B. C., Bartholomeu, D. C., Melo, M. B., Ropert, C., Rodrigues, M. M., & Gazzinelli, R. T. (2010) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399410001560 · Cited by 170
Activation of Toll-Like Receptor (TLR)2, TLR4, and TLR9 in the Mammalian Cornea Induces MyD88-Dependent Corneal Inflammation
Johnson, A. C., Heinzel, F. P., Diaconu, E., Sun, Y., Hise, A. G., Golenbock, D. T., Lass, J. H., & Pearlman, E. M. (2005) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.04-1077 · Cited by 167
How important are Toll‐like receptors for antimicrobial responses?
Carpenter, S., & O'Neill, L. A. J. (2007) · Cellular Microbiology · doi:10.1111/j.1462-5822.2007.00965.x · Cited by 182
“TLR9 has been shown to be able to respond to MCMV and herpes simplex virus (HSV), presumably through the presence of unmethylated CpG within these viral genomes (Krug et al., 2004).”
BackgroundInfluential
Identification of Toll-like receptor 4 (Tlr4) as the sole conduit for LPS signal transduction: genetic and evolutionary studies
Beutler, B., Du, X., & Poltorak, A. N. (2001) · Journal of Endotoxin Research · doi:10.1177/09680519010070040901 · Cited by 167
Immunotherapy of sepsis
van der Poll, T. (2001) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(01)00093-7 · Cited by 167
Biology of Toll receptors: lessons from insects and mammals
Imler, J., & Zheng, L. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0403160 · Cited by 173
“or unmethylated CpG motifs found in bacterial DNA (TLR9) [42] (Fig.”
BackgroundInfluential
Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity
Sridharan, A., Esposo, M., Kaushal, K., Tay, J., Osann, K., Agrawal, S., Gupta, S., & Agrawal, A. (2011) · AGE · doi:10.1007/s11357-010-9191-3 · Cited by 165
“TLR9 recognizes unmethylated 2′-deoxyribo (cytidine–phosphate–guanosine) (CpG) DNA motifs (Hemmi et al. 2000) that are present at high frequencies in pathogens such as viruses and bacteria but are rare in vertebrates.”
Background
Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders
Huang, Y., Liu, B., Sinha, S. C., Amin, S., & Gan, L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00672-x · Cited by 164
Immunohistochemical localization of Toll‐like receptors 1–10 in periodontitis
Beklen, A., Hukkanen, M., Rautemaa‐Richardson, R., & Konttinen, Y. T. (2008) · Oral Microbiology and Immunology · doi:10.1111/j.1399-302x.2008.00448.x · Cited by 165
BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation
Eckl‐Dorna, J., & Batista, F. D. (2009) · Blood · doi:10.1182/blood-2008-10-185421 · Cited by 164
Unique features of chicken Toll-like receptors
Keestra, A. M., de Zoete, M. R., Bouwman, L. I., Vaezirad, M. M., & van Putten, J. P. M. (2013) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2013.04.009 · Cited by 176
Importance of Nucleic Acid Recognition in Inflammation and Autoimmunity
Barrat, F. J., Elkon, K. B., & Fitzgerald, K. A. (2015) · Annual Review of Medicine · doi:10.1146/annurev-med-052814-023338 · Cited by 164
Principles of intracellular viral recognition
Saito, T., & Gale, M. (2006) · Current Opinion in Immunology · doi:10.1016/j.coi.2006.11.003 · Cited by 166
Human Toll‐like receptor‐dependent induction of interferons in protective immunity to viruses
Zhang, S., Jouanguy, E., Sancho‐Shimizu, V., von Bernuth, H., Yang, K., Abel, L., Pïcard, C., Puel, A., & Casanova, J. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00564.x · Cited by 171
“Stetson DB, Medzhitov R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response.”
BackgroundInfluential
Myeloid Differentiation Factor 88–Dependent and –Independent Pathways in Toll‐Like Receptor Signaling
Akira, S., & Hoshino, K. (2003) · The Journal of Infectious Diseases · doi:10.1086/374749 · Cited by 170
“TLR9-deficient mice were generated and analyzed [34].”
Self-citation
A Dipalmitoylated Lipoprotein from Mycoplasma pneumoniae Activates NF-κB through TLR1, TLR2, and TLR6
Shimizu, T., Kida, Y., & Kuwano, K. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.7.4641 · Cited by 165
Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy
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“TLRs located in cytoplasm, however, detect viral or microbial nucleic acids as well as the mitochondrial nucleic acids associated with cell injury (23).”
Background
TLR9 ligation in pancreatic stellate cells promotes tumorigenesis
Zambirinis, C. P., Levie, E., Nguy, S., Avanzi, A., Barilla, R., Xu, Y., Seifert, L., Daley, D., Greco, S. H., Deutsch, M., et al. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20142162 · Cited by 167
Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis
Mortaz, E., Adcock, I. M., Tabarsi, P., Masjedi, M. R., Mansouri, D., Velayati, A. A., Casanova, J., & Barnes, P. J. (2014) · Journal of Clinical Immunology · doi:10.1007/s10875-014-0103-7 · Cited by 180
“For example, stimulation of the TLR9 pathway by CpGODN induces CXCL8 production by human neutrophils via the generation of ONOO− [47, 48].”
Background
Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis
Roduit, C., Wohlgensinger, J., Frei, R., Bitter, S., Bieli, C., Loeliger, S., Büchele, G., Riedler, J., Dalphin, J., Remes, S., et al. (2010) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2010.10.010 · Cited by 164
The role of Toll-like receptor signalling in the pathogenesis of arthritis
Brentano, F., Kyburz, D., Schorr, O., Gay, R., & Gay, S. (2005) · Cellular Immunology · doi:10.1016/j.cellimm.2005.04.018 · Cited by 168

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

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