The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors
Open accessAbstract
Toll-like receptors (TLRs) have been shown to participate in the recognition of pathogens by the innate immune system, but it is not clear how a restricted family of receptors has the capacity to recognize the wide spectrum of TLR stimuli known to exist. We report here that two members of the TLR family, TLR2 and TLR6, together coordinate macrophage activation by Gram-positive bacteria and the yeast cell-wall particle, zymosan. TLR6 and TLR2 both are recruited to the macrophage phagosome, where they recognize peptidoglycan, a Gram-positive pathogen component. By contrast, TLR2 recognizes another component, bacterial lipopeptide, without TLR6. The requirement for TLR cooperation is supported by the finding that TLR2 needs a partner to activate tumor necrosis factor-α production in macrophages. Dimerization of the cytoplasmic domain of TLR2 does not induce tumor necrosis factor-α production in macrophages, whereas similar dimerization of the TLR4 cytoplasmic domain does. We show that the cytoplasmic domain of TLR2 can form functional pairs with TLR6 or TLR1, and this interaction leads to cytokine induction. Thus, the cytoplasmic tails of TLRs are not functionally equivalent, with certain TLRs requiring assembly into heteromeric complexes, whereas others are active as homomeric complexes. Finally, we show that TLR6, TLR2, and TLR1 are recruited to macrophage phagosomes that contain IgG-coated erythrocytes that do not display microbial components. The data suggest that TLRs sample the contents of the phagosome independent of the nature of the contents, and can establish a combinatorial repertoire to discriminate among the large number of pathogen-associated molecular patterns found in nature.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Cited by
Janeway, C. A., & Medzhitov, R. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.083001.084359 · Cited by 8,394
Akira, S., & Takeda, K. (2004) · Nature reviews. Immunology · doi:10.1038/nri1391 · Cited by 8,312
Takeda, K., Kaisho, T., & Akira, S. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141126 · Cited by 6,143
Toll-like receptors: critical proteins linking innate and acquired immunity
Akira, S., Takeda, K., & Kaisho, T. (2001) · Nature Immunology · doi:10.1038/90609 · Cited by 4,777
Toll-like receptors and innate immunity
Medzhitov, R. (2001) · Nature Reviews Immunology · doi:10.1038/35100529 · Cited by 4,308
Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., Kono, H., Rock, K. L., Fitzgerald, K. A., & Latz, E. (2008) · Nature Immunology · doi:10.1038/ni.1631 · Cited by 3,065
The immunopathogenesis of sepsis
Cohen, J. (2002) · Nature · doi:10.1038/nature01326 · Cited by 2,742
The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling
O'Neill, L. A. J., & Bowie, A. G. (2007) · Nature Reviews Immunology · doi:10.1038/nri2079 · Cited by 2,667
Kadowaki, N., Ho, S., Antonenko, S., de Waal Malefyt, R., Kastelein, R. A., Bazan, F., & Liu, Y.-J. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.6.863 · Cited by 1,964
Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron
Flo, T. H., Smith, K. D., Sato, S., Rodriguez, D. J., Holmes, M. A., Strong, R. K., Akira, S., & Aderem, A. (2004) · Nature · doi:10.1038/nature03104 · Cited by 1,877
Self-citationThe history of toll-like receptors - redefining innate immunity
O'Neill, L. A. J., Golenbock, D., & Bowie, A. G. (2013) · Nature reviews. Immunology · doi:10.1038/nri3446 · Cited by 1,765
Stewart, C. R., Stuart, L. M., Wilkinson, K., van Gils, J. M., Deng, J., Halle, A., Rayner, K. J., Boyer, L., Zhong, R., Frazier, W. A., et al. (2010) · Nature Immunology · doi:10.1038/ni.1836 · Cited by 1,513
“We therefore tested whether fibrillar β-amyloid peptide (1-42) (Aβ1-42) could activate TLR4-TLR6 signaling via CD36.”
BackgroundNovel Signal Transduction Pathway Utilized by Extracellular HSP70
Asea, A., Rehli, M., Kabingu, E., Boch, J. A., Baré, O., Auron, P. E., Stevenson, M. A., & Calderwood, S. K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200497200 · Cited by 1,510
Innate Immune Pattern Recognition: A Cell Biological Perspective
Brubaker, S. W., Bonham, K. S., Zanoni, I., & Kagan, J. C. (2015) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112240 · Cited by 1,475
Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis
Sanjuan, M. A., Dillon, C. P., Tait, S. W. G., Moshiach, S., Dorsey, F., Connell, S., Komatsu, M., Tanaka, K., Cleveland, J. L., Withoff, S., et al. (2007) · Nature · doi:10.1038/nature06421 · Cited by 1,347
Dectin-1: a signalling non-TLR pattern-recognition receptor
Brown, G. D. (2006) · Nature Reviews Immunology · doi:10.1038/nri1745 · Cited by 1,158
Phagocytosis of Microbes: Complexity in Action
Underhill, D. M., & Ozinsky, A. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.103001.114744 · Cited by 1,124
Self-citationCandida albicans morphogenesis and host defence: discriminating invasion from colonization
Gow, N. A. R., van de Veerdonk, F. L., Brown, A. J. P., & Netea, M. G. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2711 · Cited by 888
CD36 is a sensor of diacylglycerides
Hoebe, K., Georgel, P., Rutschmann, S., Du, X., Mudd, S., Crozat, K., Sovath, S., Shamel, L., Hartung, T., Zähringer, U., et al. (2005) · Nature · doi:10.1038/nature03253 · Cited by 873
Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848
Jurk, M., Heil, F., Vollmer, J., Schetter, C., Krieg, A. M., Wagner, H., Lipford, G., & Bauer, S. (2002) · Nature Immunology · doi:10.1038/ni0602-499 · Cited by 838
Signals of recent positive selection in a worldwide sample of human populations
Pickrell, J. K., Coop, G., Novembre, J., Kudaravalli, S., Li, J. Z., Absher, D., Srinivasan, B. S., Barsh, G. S., Myers, R. M., Feldman, M. W., et al. (2009) · Genome Research · doi:10.1101/gr.087577.108 · Cited by 717
Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function
Cario, E., Gerken, G., & Podolsky, D. K. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.02.056 · Cited by 697
Information processing during phagocytosis
Underhill, D. M., & Goodridge, H. S. (2012) · Nature Reviews Immunology · doi:10.1038/nri3244 · Cited by 616
Self-citationModulation of atherosclerosis in mice by Toll-like receptor 2
Mullick, A. E. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25482 · Cited by 549
Bellocchio, S., Montagnoli, C., Bozza, S., Gaziano, R., Rossi, G., Mambula, S. S., Vecchi, A., Mantovani, A., Levitz, S. M., & Romani, L. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.5.3059 · Cited by 515
Peptidoglycan recognition by the innate immune system
Wolf, A. J., & Underhill, D. M. (2018) · Nature Reviews Immunology · doi:10.1038/nri.2017.136 · Cited by 469
Self-citationUse of defined TLR ligands as adjuvants within human vaccines
Duthie, M. S., Windish, H. P., Fox, C. B., & Reed, S. G. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00978.x · Cited by 437
Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors
Harding, C. V., & Boom, W. H. (2010) · Nature Reviews Microbiology · doi:10.1038/nrmicro2321 · Cited by 435
Melmed, G., Thomas, L. S., Lee, N., Tesfay, S. Y., Lukasek, K., Michelsen, K. S., Zhou, Y., Hu, B., Arditi, M., & Abreu, M. T. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.3.1406 · Cited by 431
Sanlioglu, S., Williams, C. M., Samavati, L., Butler, N. S., Wang, G., McCray, P. B., Ritchie, T. C., Hunninghake, G. W., Zandi, E., & Engelhardt, J. F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102061200 · Cited by 395
Age-Associated Defect in Human TLR-1/2 Function
van Duin, D., Mohanty, S., Thomas, V., Ginter, S., Montgomery, R. R., Fikrig, E., Allore, H. G., Medzhitov, R., & Shaw, A. C. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.2.970 · Cited by 352
González, H., Elgueta, D., Montoya, A., & Pacheco, R. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.07.012 · Cited by 352
LeBouder, E., Rey-Nores, J. E., Rushmere, N. K., Grigorov, M., Lawn, S. D., Affolter, M., Griffin, G. E., Ferrara, P., Schiffrin, E. J., Morgan, B. P., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.12.6680 · Cited by 340
Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability
Randow, F., & Seed, B. (2001) · Nature Cell Biology · doi:10.1038/ncb1001-891 · Cited by 316
Daniele, S. G., Béraud, D., Davenport, C., Cheng, K., Yin, H., & Maguire-Zeiss, K. A. (2015) · Science Signaling · doi:10.1126/scisignal.2005965 · Cited by 303
Microbial recognition by Toll-like receptors
Takeda, K., & Akira, S. (2004) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2003.10.002 · Cited by 285
Cutting Edge: TLR2 Is a Functional Receptor for Acute-Phase Serum Amyloid A
Cheng, N., He, R., Tian, J., Ye, P. P., & Ye, R. D. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.1.22 · Cited by 284
Candida albicans Phospholipomannan Is Sensed through Toll‐Like Receptors
Jouault, T., Ibata‐Ombetta, S., Takeuchi, O., Trinel, P., Sacchetti, P., Lefebvre, P., Akira, S., & Poulain, D. (2003) · The Journal of Infectious Diseases · doi:10.1086/375784 · Cited by 274
Intestinal myofibroblasts in innate immune responses of the intestine
Otte, J.-M., Rosenberg, I. M., & Podolsky, D. K. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)00403-7 · Cited by 242
Screening of innate immune receptors in neurodegenerative diseases: A similar pattern
Letiembre, M., Liu, Y., Walter, S., Hao, W., Pfander, T., Wrede, A., Schulz-Schaeffer, W., & Fassbender, K. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.08.018 · Cited by 228
de Bouteiller, O., Merck, E., Hasan, U. A., Hubac, S., Benguigui, B., Trinchieri, G., Bates, E. E. M., & Caux, C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507163200 · Cited by 220
Toll-Like Receptor 2 Is Required for Optimal Control of Listeria monocytogenes Infection
Torres, D., Barrier, M., Bihl, F., Quesniaux, V. J. F., Maillet, I., Akira, S., Ryffel, B., & Erard, F. (2004) · Infection and Immunity · doi:10.1128/iai.72.4.2131-2139.2004 · Cited by 191
A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia
Guida, C., Altamura, S., Klein, F. A., Galy, B., Boutros, M., Ulmer, A. J., Hentze, M. W., & Muckenthaler, M. U. (2015) · Blood · doi:10.1182/blood-2014-08-595256 · Cited by 173
Ito, H., & Hamerman, J. A. (2012) · European Journal of Immunology · doi:10.1002/eji.201141679 · Cited by 173
Host–microbe interactions: innate pattern recognition of fungal pathogens
van de Veerdonk, F. L., Kullberg, B. J., van der Meer, J. W., Gow, N. A., & Netea, M. G. (2008) · Current Opinion in Microbiology · doi:10.1016/j.mib.2008.06.002 · Cited by 169
Viruses as adjuvants for autoimmunity: evidence from Coxsackievirus‐induced myocarditis
Fairweather, D., Frisancho‐Kiss, S., & Rose, N. R. (2005) · Reviews in Medical Virology · doi:10.1002/rmv.445 · Cited by 155
Ip, W. K. E., Sokolovska, A., Charriere, G. M., Boyer, L., Dejardin, S., Cappillino, M. P., Yantosca, L. M., Takahashi, K., Moore, K. J., Lacy-Hulbert, A., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000110 · Cited by 148
Toll-like receptor signaling in the lysosomal pathways
Sanjuan, M. A., Milasta, S., & Green, D. R. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00732.x · Cited by 137
The Interleukin‐1 Receptor Family
Boraschi, D., & Tagliabue, A. (2006) · Vitamins & Hormones · doi:10.1016/s0083-6729(06)74009-2 · Cited by 133
Kumar, A., Zhang, J., & Yu, F.-S. X. (2004) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.04-0467 · Cited by 127
Candida albicans Interactions with Mucosal Surfaces during Health and Disease
Nikou, S.-A., Kichik, N., Brown, R., Ponde, N., Ho, J., Naglik, J., & Richardson, J. (2019) · Pathogens · doi:10.3390/pathogens8020053 · Cited by 103
Ye, J., Xie, C., Wang, C., Huang, J., Yin, Z., Heng, B. C., Chen, X., & Shen, W. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2021.04.017 · Cited by 97
Xu, Q., Yajima, T., Li, W., Saito, K., Ohshima, Y., & Yoshikai, Y. (2006) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.2006.02401.x · Cited by 94
An Essential Role for RIG-I in Toll-like Receptor-Stimulated Phagocytosis
Kong, L., Sun, L., Zhang, H., Liu, Q., Liu, Y., Qin, L., Shi, G., Hu, J.-H., Xu, A., Sun, Y.-P., et al. (2009) · Cell Host & Microbe · doi:10.1016/j.chom.2009.06.008 · Cited by 86
Zhao, H., Hemmi, H., Akira, S., Cheng, S. H., Scheule, R. K., & Yew, N. S. (2004) · Molecular Therapy · doi:10.1016/j.ymthe.2003.11.012 · Cited by 85
Prophylactic and therapeutic implications of toll-like receptor ligands
Hedayat, M., Takeda, K., & Rezaei, N. (2012) · Medicinal Research Reviews · doi:10.1002/med.20214 · Cited by 76
Mutation-selective tumor remission with Ras-targeted, whole yeast-based immunotherapy
Lu, Y., Bellgrau, D., Dwyer-Nield, L. D., Malkinson, A. M., Duke, R. C., Rodell, T. C., & Franzusoff, A. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1487 · Cited by 71
The role of toll-like receptors in macrophages
McCoy, C. (2008) · Frontiers in Bioscience · doi:10.2741/2660 · Cited by 69
Identification of novel mechanisms involved in generating localized vulvodynia pain
Falsetta, M. L., Foster, D. C., Woeller, C. F., Pollock, S. J., Bonham, A. D., Haidaris, C. G., Stodgell, C. J., & Phipps, R. P. (2015) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2015.02.002 · Cited by 69
Post-translational processing targets functionally diverse proteins in Mycoplasma hyopneumoniae
Tacchi, J. L., Raymond, B. B. A., Haynes, P. A., Berry, I. J., Widjaja, M., Bogema, D. R., Woolley, L. K., Jenkins, C., Minion, F. C., Padula, M. P., et al. (2016) · Open Biology · doi:10.1098/rsob.150210 · Cited by 62
Candida species in cystic fibrosis: A road less travelled
Chotirmall, S. H., Greene, C. M., & McElvaney, N. G. (2010) · Medical Mycology · doi:10.3109/13693786.2010.503320 · Cited by 61
Choteau, L., Vancraeyneste, H., Le Roy, D., Dubuquoy, L., Romani, L., Jouault, T., Poulain, D., Sendid, B., Calandra, T., Roger, T., et al. (2017) · Gut Pathogens · doi:10.1186/s13099-017-0158-0 · Cited by 59
Wiener, E. (2003) · Hematology · doi:10.1080/1024533031000081414 · Cited by 34
Wilson, C. L., Mann, J., Walsh, M., Perrugoria, M. J., Oakley, F., Wright, M. C., Brignole, C., Di Paolo, D., Perri, P., Ponzoni, M., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0083391 · Cited by 31
Self-citationNaglik, J. R. (2014) · New Journal of Science · doi:10.1155/2014/390241 · Cited by 29
The Role of Toll-Like Receptors in Osteoclastogenesis
Yim, M. (2020) · Journal of Bone Metabolism · doi:10.11005/jbm.2020.27.4.227 · Cited by 28
Toll-like receptor 2 confers partial neuroprotection during prion disease
Carroll, J. A., Race, B., Williams, K., & Chesebro, B. (2018) · PLOS ONE · doi:10.1371/journal.pone.0208559 · Cited by 22
Metadata
- Authors
- Ozinsky, A., Underhill, D. M., Fontenot, J. D., Hajjar, A. M., Smith, K. D., Wilson, C. B., Schroeder, L., & Aderem, A.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2000-11-28
- Volume
- 97
- Issue
- 25
- Pages
- 13766-13771
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2016862474
- Cited by
- 2,085
- References
- 1
- FWCI
- 37.58
- Type
- journal article
- Language
- en
- Open access
- green
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
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.