mRNA is an endogenous ligand for toll-like receptor 3
Open accessAbstract
Toll-like receptors (TLRs) are the basic signaling receptors of the innate immune system. They are activated by molecules associated with pathogens or injured host cells and tissue. TLR3 has been shown to respond to double stranded (ds) RNA, a replication intermediary for many viruses. Here we present evidence that heterologous RNA released from or associated with necrotic cells or generated by in vitro transcription also stimulates TLR3 and induces immune activation. To assess RNA-mediated TLR3 activation, human embryonic kidney 293 cells stably expressing TLR3 and containing a nuclear factor-kappaB-dependent luciferase reporter were generated. Exposing these cells to in vitro transcribed RNA resulted in a TLR3-dependent induction of luciferase activity and interleukin-8 secretion. Treatment with in vitro transcribed mRNA activated nuclear factor-kappaB via TLR3 through a process that was dose-dependent and involved tyrosine phosphorylation. Furthermore, in vitro transcribed natural or 2'-fluoro-substituted mRNA induced the expression of TLR3, interferon regulatory factor-1, tumor necrosis factor-alpha, and interleukin-1 receptor-associated kinase-M mRNA in human dendritic cells (DCs). DCs responded to mRNA treatment by expressing activation markers, and this maturation was inhibited by antagonistic TLR3-specific antibody. Endogenous RNA released from or associated with necrotic cells also stimulated DCs, leading to interferon-alpha secretion, which could be abolished by pretreatment of necrotic cells with RNase. These results demonstrate that RNA, likely through secondary structure, is a potent host-derived activator of TLR3. This finding has potential physiologic relevance because RNA escaping from damaged tissue or contained within endocytosed cells could serve as an endogenous ligand for TLR3 that induces or otherwise modulates immune responses.
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Not only viral RNA, but also endogenous mRNA associated with apoptotic cells and in vitro transcribed mRNA can bind and activate TLR3, TLR7 and TLR8.
“not only viral RNA, but also endogenous mRNA associated with apoptotic cells as well as in vitro transcribed (IVT) mRNA could bind and activate TLR3, TLR7 and TLR8 [4,5]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [4]
Cites
Mfold web server for nucleic acid folding and hybridization prediction
Zuker, M. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg595 · Cited by 13,404 · see citing works
Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3
Alexopoulou, L., Holt, A. C., Medzhitov, R., & Flavell, R. A. (2001) · Nature · doi:10.1038/35099560 · Cited by 6,129 · see citing works
Tolerance, Danger, and the Extended Family
Matzinger, P. (1994) · Annual Review of Immunology · doi:10.1146/annurev.iy.12.040194.005015 · Cited by 4,848 · see citing works
Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information
Zuker, M., & Stiegler, P. (1981) · Nucleic Acids Research · doi:10.1093/nar/9.1.133 · Cited by 3,604 · see citing works
Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging
Mori, S., Crain, B. J., Chacko, V. P., & van Zijl, P. C. M. (1999) · Annals of Neurology · doi:10.1002/1531-8249(199902)45:2 · Cited by 3,479 · see citing works
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 · see citing works
Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors
Leadbetter, E. A., Rifkin, I. R., Hohlbaum, A. M., Beaudette-Zlatanova, B. C., Shlomchik, M. J., & Marshak‐Rothstein, A. (2002) · Nature · doi:10.1038/416603a · Cited by 1,899 · see citing works
IRF Family of Transcription Factors as Regulators of Host Defense
Taniguchi, T., Ogasawara, K., Takaoka, A., & Tanaka, N. (2001) · Annual Review of Immunology · doi:10.1146/annurev.immunol.19.1.623 · Cited by 1,658 · see citing works
Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4
Termeer, C., Benedix, F., Sleeman, J., Fieber, C., Voith, U., Ahrens, T., Miyake, K., Freudenberg, M., Galanos, C., & Simon, J. C. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20001858 · Cited by 1,378 · see citing works
Cd8+ but Not Cd8− Dendritic Cells Cross-Prime Cytotoxic T Cells in Vivo
den Haan, J. M. M., Lehar, S. M., & Bevan, M. J. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.12.1685 · Cited by 1,319 · see citing works
Basu, S., Binder, R. J., Suto, R., Anderson, K. M., & Srivastava, P. K. (2000) · International Immunology · doi:10.1093/intimm/12.11.1539 · Cited by 1,305 · see citing works
IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling
Kobayashi, K. S., Hernandez, L. D., Galán, J. E., Janeway, C. A., Medzhitov, R. M., & Flavell, R. A. (2002) · Cell · doi:10.1016/s0092-8674(02)00827-9 · Cited by 1,289 · see citing works
Yamamoto, M., Sato, S., Mori, K., Hoshino, K., Takeuchi, O., Takeda, K., & Akira, S. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.12.6668 · Cited by 1,227 · see citing works
Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T., & Seya, T. (2003) · Nature Immunology · doi:10.1038/ni886 · Cited by 1,208 · see citing works
Gordon, S. (2002) · Cell · doi:10.1016/s0092-8674(02)01201-1 · Cited by 1,153 · see citing works
Muzio, M., Bosisio, D., Polentarutti, N., D’Amico, G., Stoppacciaro, A., Mancinelli, R., Veer, C. V. ′., Pentón‐Rol, G., Ruco, L., Allavena, P., et al. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.11.5998 · Cited by 1,058 · see citing works
TIRAP: an adapter molecule in the Toll signaling pathway
Horng, T., Barton, G. M., & Medzhitov, R. M. (2001) · Nature Immunology · doi:10.1038/ni0901-835 · Cited by 970 · see citing works
Fibrinogen Stimulates Macrophage Chemokine Secretion Through Toll-Like Receptor 4
Smiley, S. T., King, J. A., & Hancock, W. W. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.5.2887 · Cited by 946 · see citing works
Toll-Like Receptor 4-Dependent Activation of Dendritic Cells by β-Defensin 2
Biragyn, A., Ruffini, P. A., Leifer, C. A., Klyushnenkova, E., Shakhov, A., Chertov, O., Shirakawa, A., Farber, J. M., Segal, D. M., Oppenheim, J. J., et al. (2002) · Science · doi:10.1126/science.1075565 · Cited by 904 · see citing works
TLR4, but not TLR2, mediates IFN-β–induced STAT1α/β-dependent gene expression in macrophages
Toshchakov, V. Y., Jones, B. W., Perera, P., Thomas, K., Cody, M. J., Zhang, S., Williams, B. R. G., Major, J. A., Hamilton, T. A., Fenton, M. J., et al. (2002) · Nature Immunology · doi:10.1038/ni774 · Cited by 803 · see citing works
Matsuyama, T., Kimura, T., Kitagawa, M., Pfeffer, K., Kawakami, T., Watanabe, N., Kündig, T. M., Amakawa, R., Kishihara, K., Wakeham, A., et al. (1993) · Cell · doi:10.1016/s0092-8674(05)80086-8 · Cited by 649 · see citing works
Johnson, G. B., Brunn, G. J., Kodaira, Y., & Platt, J. L. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.10.5233 · Cited by 648 · see citing works
Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells
Visintin, A., Mazzoni, A., Spitzer, J. H., Wyllie, D. H., Dower, S., & Segal, D. M. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.1.249 · Cited by 611 · see citing works
Mutation of DNASE1 in people with systemic lupus erythematosus
Yasutomo, K., Horiuchi, T., Kagami, S., Tsukamoto, H., Hashimura, C., Urushihara, M., & Kuroda, Y. (2001) · Nature Genetics · doi:10.1038/91070 · Cited by 598 · see citing works
Heiser, A., Coleman, D., Dannull, J., Yancey, D., Maurice, M. A., Lallas, C. D., Dahm, P., Niedzwiecki, D., Gilboa, E., & Vieweg, J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214364 · Cited by 562 · see citing works
Beg, A. A. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02317-7 · Cited by 495 · see citing works
Heiser, A., Coleman, D., Dannull, J., Yancey, D. R., Maurice, M. A., Lallas, C. D., Dahm, P., Niedzwiecki, D., Gilboa, E., & Vieweg, J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci14364 · Cited by 487 · see citing works
Matsumoto, M., Kikkawa, S., Kohase, M., Miyake, K., & Seya, T. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00380-7 · Cited by 451 · see citing works
TOLL-like receptors linking innate and adaptive immune response
Werling, D., & Jungi, T. W. (2002) · Veterinary Immunology and Immunopathology · doi:10.1016/s0165-2427(02)00228-3 · Cited by 403 · see citing works
Nair, S. K., Boczkowski, D., Morse, M., Cumming, R. I., Lyerly, H. K., & Gilboa, E. (1998) · Nature Biotechnology · doi:10.1038/nbt0498-364 · Cited by 398 · see citing works
Matzinger, P. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb03118.x · Cited by 360 · see citing works
Nair, S. K., Heiser, A., Boczkowski, D., Majumdar, A. S., Naoe, M., LEBKOWSKI, J. S., Vieweg, J., & Gilboa, E. (2000) · Nature Medicine · doi:10.1038/79519 · Cited by 348 · see citing works
The dsRNA binding protein family: critical roles, diverse cellular functions
Saunders, L. R., & Barber, G. N. (2003) · The FASEB Journal · doi:10.1096/fj.02-0958rev · Cited by 338 · see citing works
Toll-Like Receptors and Their Ligands
Barton, G. M., & Medzhitov, R. M. (2002) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-59430-4_5 · Cited by 302 · see citing works
Plevy, S. E., Gemberling, J. H. M., Hsu, S., Dorner, A. J., & Smale, S. T. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.8.4572 · Cited by 302 · see citing works
Datta, S. K., Redecke, V., Prilliman, K. R., Takabayashi, K., Corr, M., Tallant, T. C., DiDonato, J. A., Dziarski, R., Akira, S., Schoenberger, S. P., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.8.4102 · Cited by 300 · see citing works
Guillot, L., Balloy, V., McCormack, F. X., Golenbock, D. T., Chignard, M., & Si‐Tahar, M. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.12.5989 · Cited by 299 · see citing works
Rosenberg, H. F., & Domachowske, J. B. (2001) · Journal of Leukocyte Biology · doi:10.1189/jlb.70.5.691 · Cited by 287 · see citing works
IFNs activate toll-like receptor gene expression in viral infections
Miettinen, M., Sareneva, T., Julkunen, I., & Matikainen, S. (2001) · Genes and Immunity · doi:10.1038/sj.gene.6363791 · Cited by 282 · see citing works
Heat Shock Proteins as Ligands of Toll-Like Receptors
Vabulas, R. M., Wagner, H., & Schild, H. (2002) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-59430-4_11 · Cited by 276 · see citing works
Cellular Events Mediated by Lipopolysaccharide-stimulated Toll-like Receptor 4
Yang, H., Young, D. W., Gusovsky, F., & Chow, J. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002896200 · Cited by 269 · see citing works
Kröger, A., Köster, M., Schroeder, K., Häuser, H., & Mueller, P. P. (2002) · Journal of Interferon & Cytokine Research · doi:10.1089/107999002753452610 · Cited by 265 · see citing works
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 · see citing works
Nair, S. K., Morse, M. A., Boczkowski, D., Cumming, R. I., Vasović, L. V., Gilboa, E., & Lyerly, H. K. (2002) · Annals of Surgery · doi:10.1097/00000658-200204000-00013 · Cited by 205 · see citing works
Heiser, A., Maurice, M. A., Yancey, D. R., Wu, N., Dahm, P., Pruitt, S. K., Boczkowski, D., Nair, S. K., Ballo, M. S., Gilboa, E., et al. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.5.2953 · Cited by 198 · see citing works
Jiang, Z.-F., Johnson, H., Nie, H., Qin, J.-Z., Bird, T., & Li, X.-X. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212112200 · Cited by 186 · see citing works
Weissman, D., Ni, H., Scales, D. A., Dude, A., Capodici, J., McGibney, K., Abdool, A. J., Isaacs, S. N., Cannon, G., & Karikó, K. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.8.4710 · Cited by 178 · see citing works
Self-citationToll-Like Receptor 3 Mediates a More Potent Antiviral Response Than Toll-Like Receptor 4
Doyle, S. E., O’Connell, R. M., Vaidya, S. A., Chow, E. K., Yee, K. T., & Cheng, G. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3565 · Cited by 177 · see citing works
Nucleosome remodeling at the IL-12 p40 promoter is a TLR-dependent, Rel-independent event
Weinmann, A. S., Mitchell, D. M., Sanjabi, S., Bradley, M. N., Hoffmann, A., Liou, H.-C., & Smale, S. T. (2001) · Nature Immunology · doi:10.1038/83168 · Cited by 161 · see citing works
Sato, M., Taniguchi, T., & Tanaka, N. (2001) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(00)00032-0 · Cited by 161 · see citing works
RNA sequestration to pathological lesions of neurodegenerative diseases
Ginsberg, S. D., Galvin, J. E., Chiu, T.-L. S., Lee, V. M. ‐., Masliah, E., & Trojanowski, J. Q. (1998) · Acta Neuropathologica · doi:10.1007/s004010050923 · Cited by 142 · see citing works
Sarkar, S. N., Smith, H., Rowe, T. M., & Sen, G. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c200655200 · Cited by 117 · see citing works
Cross-Presentation of Antigens by Dendritic Cells
Heath, W. R., Carbone, F., & Belz, G. T. (2002) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v22.i5-6.50 · Cited by 70 · see citing works
Eilat, D., & Anderson, W. F. (1994) · Molecular Immunology · doi:10.1016/0161-5890(94)90154-6 · Cited by 61 · see citing works
Ni, H., Capodici, J., Cannon, G., Communi, D., Boeynaems, J., Karikó, K., & Weissman, D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110729200 · Cited by 60 · see citing works
Self-citationPhosphate-enhanced transfection of cationic lipid-complexed mRNA and plasmid DNA
Karikó, K., Kuo, A., Barnathan, E. S., & Langer, D. J. (1998) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/s0005-2736(97)00238-1 · Cited by 48 · see citing works
Self-citationShinobu, N., Iwamura, T., Yoneyama, M., Yamaguchi, K., Suhara, W., Fukuhara, Y., Amano, F., & Fujita, T. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02636-4 · Cited by 48 · see citing works
βAPP and Furin mRNA Concentrates in Immature Senile Plaques in the Brain of Alzheimer Patients
Marcinkiewicz, M. M. (2002) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/61.9.915 · Cited by 37 · see citing works
Cross-Presentation of Cell-Associated Antigens by Dendritic Cells
Larsson, M., Fonteneau, J., & Bhardwaj, N. (2003) · Current topics in microbiology and immunology · doi:10.1007/978-3-662-06508-2_12 · Cited by 34 · see citing works
Smith, C. L., Wolford, R. G., O’Neill, T. B., & Hager, G. L. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.7.0482 · Cited by 25 · see citing works
Kalina (2002) · doi:10.1002/1521-4141(200209)32:9
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1 of the 63 references couldn’t be matched to a known paper.
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Immunogenic cell death and DAMPs in cancer therapy
Krysko, D. V., Garg, A. D., Kaczmarek, A., Krysko, O., Agostinis, P., & Vandenabeele, P. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3380 · Cited by 3,223 · see citing works
Sterile inflammation: sensing and reacting to damage
Chen, G. Y., & Nuñez, G. (2010) · Nature Reviews Immunology · doi:10.1038/nri2873 · Cited by 3,051 · see citing works
Karikó, K., Buckstein, M., Ni, H., & Weissman, D. (2005) · Immunity · doi:10.1016/j.immuni.2005.06.008 · Cited by 2,728 · see citing works
Self-citationKarikó, K., Muramatsu, H., Welsh, F. A., Ludwig, J., Kato, H., Akira, S., & Weissman, D. (2008) · Molecular Therapy · doi:10.1038/mt.2008.200 · Cited by 1,930 · see citing works
Self-citationAstrocytes are active players in cerebral innate immunity
Farina, C., Aloisi, F., & Meinl, E. (2007) · Trends in Immunology · doi:10.1016/j.it.2007.01.005 · Cited by 1,304 · see citing works
Mechanisms of Age-Related Macular Degeneration
Ambati, J., & Fowler, B. J. (2012) · Neuron · doi:10.1016/j.neuron.2012.06.018 · Cited by 1,029 · see citing works
Jongbloed, S. L., Kassianos, A. J., McDonald, K. J., Clark, G. J., Ju, X., Angel, C. E., Chen, C. J., Dunbar, P. R., Wadley, R. B., Jeet, V., et al. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20092140 · Cited by 1,019 · see citing works
DAMPening Inflammation by Modulating TLR Signalling
Piccinini, A. M., & Midwood, K. S. (2010) · Mediators of Inflammation · doi:10.1155/2010/672395 · Cited by 974 · see citing works
Barrat, F. J., Meeker, T., Gregorio, J. D., Chan, J. H., Uematsu, S., Akira, S., Chang, B., Duramad, O., & Coffman, R. L. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050914 · Cited by 932 · see citing works
Modified mRNA vaccines protect against zika virus infection
Richner, J. M., Himansu, S., Dowd, K. A., Butler, S. L., Salazar, V., Fox, J. M., Julander, J. G., Tang, W. W., Shresta, S., Pierson, T. C., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.017 · Cited by 909 · see citing works
Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury
Gaudet, A. D., Popovich, P. G., & Ramer, M. S. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-110 · Cited by 903 · see citing works
Semeraro, F., Ammollo, C. T., Morrissey, J. H., Dale, G. L., Friese, P., Esmon, N. L., & Esmon, C. T. (2011) · Blood · doi:10.1182/blood-2011-03-343061 · Cited by 870 · see citing works
The role of oxidative stress during inflammatory processes
Lugrin, J., Rosenblatt‐Velin, N., Parapanov, R., & Liaudet, L. (2013) · Biological Chemistry · doi:10.1515/hsz-2013-0241 · Cited by 742 · see citing works
TLR signaling tailors innate immune responses in human microglia and astrocytes
Jack, C. S., Arbour, N., Manusow, J., Montgrain, V., Blain, M., McCrea, E., Shapiro, A., & Antel, J. P. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.7.4320 · Cited by 734 · see citing works
The immunology of acute stroke
Chamorro, Á., Meisel, A., Planas, A. M., Urra, X., van de Beek, D., & Veltkamp, R. C. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.98 · Cited by 707 · see citing works
Festjens, N., Vanden Berghe, T., & Vandenabeele, P. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.06.014 · Cited by 710 · see citing works
Endogenous ligands of Toll-like receptors
Tsan, M., & Gao, B. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0304127 · Cited by 683 · see citing works
Immune activation in brain aging and neurodegeneration: too much or too little?
Lucin, K. M., & Wyss-Coray, T. (2009) · Neuron · doi:10.1016/j.neuron.2009.08.039 · Cited by 679 · see citing works
Advances in mRNA Vaccines for Infectious Diseases
Zhang, C., Maruggi, G., Shan, H., & Li, J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00594 · Cited by 680 · see citing works
Bahl, K., Senn, J. J., Yuzhakov, O., Bulychev, A., Brito, L. A., Hassett, K. J., Laska, M. E., Smith, M., Almarsson, Ö., Thompson, J., et al. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.03.035 · Cited by 642 · see citing works
Developing mRNA-vaccine technologies
Schlake, T., Thess, A., Fotin-Mleczek, M., & Kallen, K.-J. (2012) · RNA Biology · doi:10.4161/rna.22269 · Cited by 622 · see citing works
Pathogenic mechanisms following ischemic stroke
Khoshnam, S. E., Winlow, W., Farzaneh, M., Farbood, Y., & Moghaddam, H. F. (2017) · Neurological Sciences · doi:10.1007/s10072-017-2938-1 · Cited by 618 · see citing works
Macrophage activation by endogenous danger signals
Zhang, X., & Mosser, D. (2007) · The Journal of Pathology · doi:10.1002/path.2284 · Cited by 612 · see citing works
Crystal Structure of Human Toll-Like Receptor 3 (TLR3) Ectodomain
Choe, J., Kelker, M. S., & Wilson, I. A. (2005) · Science · doi:10.1126/science.1115253 · Cited by 603 · see citing works
The tangled history of mRNA vaccines
Dolgin, E. (2021) · Nature · doi:10.1038/d41586-021-02483-w · Cited by 556 · see citing works
Endogenous toll‐like receptor ligands and their biological significance
Yu, L., Wang, L., & Chen, S. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01127.x · Cited by 531 · see citing works
Uccellini, M. B., Broughton, C., Mackay, F., Akira, S., Marshak‐Rothstein, A., & Rifkin, I. R. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031942 · Cited by 519 · see citing works
Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus
Christensen, S. R., Kashgarian, M. J., Alexopoulou, L., Flavell, R. A., Akira, S., & Shlomchik, M. J. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050338 · Cited by 516 · see citing works
Kim, J., Eygeris, Y., Gupta, M., & Sahay, G. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.014 · Cited by 514 · see citing works
Mack, M. (2017) · Matrix Biology · doi:10.1016/j.matbio.2017.11.010 · Cited by 516 · see citing works
Toll-like receptor signaling in neural plasticity and disease
Okun, E., Griffioen, K. J. S., & Mattson, M. P. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.02.005 · Cited by 513 · see citing works
The dawn of mRNA vaccines: the COVID-19 case
Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.03.043 · Cited by 504 · see citing works
The Pathogenesis of Lupus Nephritis
Lech, M., & Anders, H. (2013) · Journal of the American Society of Nephrology · doi:10.1681/asn.2013010026 · Cited by 502 · see citing works
Immunogenic cell death, DAMPs and anticancer therapeutics: An emerging amalgamation
Garg, A. D., Nowis, D., Gołąb, J., Vandenabeele, P., Krysko, D. V., & Agostinis, P. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2009.08.003 · Cited by 498 · see citing works
Molecular characteristics of immunogenic cancer cell death
Tesnière, A., Panaretakis, T., Kepp, O., Apétoh, L., Ghiringhelli, F., Zitvogel, L., & Kroemer, G. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402269 · Cited by 492 · see citing works
Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential
Hanke, M. L., & Kielian, T. (2011) · Clinical Science · doi:10.1042/cs20110164 · Cited by 493 · see citing works
Pattern recognition receptors and central nervous system repair
Kigerl, K. A., de Rivero Vaccari, J. P., Dietrich, W. D., Popovich, P. G., & Keane, R. W. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.01.001 · Cited by 490 · see citing works
Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines
Nance, K. D., & Meier, J. L. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c00197 · Cited by 466 · see citing works
Lee, Y., Jeong, M., Park, J., Jung, H., & Lee, H. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01086-x · Cited by 477 · see citing works
Karikó, K., Bhuyan, P. K., Capodici, J., & Weissman, D. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.11.6545 · Cited by 446 · see citing works
Self-citationTLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events
Cavassani, K. A., Ishii, M., Wen, H., Schaller, M. A., Lincoln, P., Lukacs, N. W., Hogaboam, C. M., & Kunkel, S. L. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20081370 · Cited by 447 · see citing works
Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses
Garg, A. D., & Agostinis, P. (2017) · Immunological Reviews · doi:10.1111/imr.12574 · Cited by 448 · see citing works
RIG-I and Other RNA Sensors in Antiviral Immunity
Chow, K. T., Gale, M., & Loo, Y. (2018) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042617-053309 · Cited by 429 · see citing works
Sioud, M. (2005) · Journal of Molecular Biology · doi:10.1016/j.jmb.2005.03.013 · Cited by 415 · see citing works
Chahal, J. S., Khan, O. F., Cooper, C. L., McPartlan, J. S., Tsosie, J. K., Tilley, L. D., Sidik, S. M., Lourido, S., Langer, R., Bavari, S., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1600299113 · Cited by 414 · see citing works
Many stimuli pull the necrotic trigger, an overview
Vanlangenakker, N., Berghe, T. V., & Vandenabeele, P. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.164 · Cited by 407 · see citing works
Toll‐like receptors, endogenous ligands, and systemic autoimmune disease
Rifkin, I. R., Leadbetter, E. A., Busconi, L., Viglianti, G. A., & Marshak‐Rothstein, A. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00239.x · Cited by 384 · see citing works
The molecular structure of the Toll-like receptor 3 ligand-binding domain
Bell, J. K., Botos, I., Hall, P. R., Askins, J., Shiloach, J., Segal, D. M., & Davies, D. R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505077102 · Cited by 380 · see citing works
TLR signaling by tumor and immune cells: a double-edged sword
Huang, B., Zhao, J., Unkeless, J. C., Feng, Z., & Xiong, H. (2008) · Oncogene · doi:10.1038/sj.onc.1210904 · Cited by 377 · see citing works
Brentano, F., Schorr, O., Gay, R. E., Gay, S., & Kyburz, D. (2005) · Arthritis & Rheumatism · doi:10.1002/art.21273 · Cited by 377 · see citing works
Targeting cancer with mRNA–lipid nanoparticles: key considerations and future prospects
Kon, E., Ad‐El, N., Hazan‐Halevy, I., Stotsky‐Oterin, L., & Peer, D. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00811-9 · Cited by 385 · see citing works
Microglia: Agents of the CNS Pro-Inflammatory Response
Rodríguez-Gómez, J. A., Kavanagh, E., Engskog-Vlachos, P., Engskog, M. K. R., Herrera, A. J., Espinosa-Oliva, A. M., Joseph, B., Hajji, N., Venero, J. L., & Burguillos, M. A. (2020) · Cells · doi:10.3390/cells9071717 · Cited by 365 · see citing works
Toll‐like receptors in central nervous system glial inflammation and homeostasis
Kielian, T. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.20767 · Cited by 363 · see citing works
Activation of the mammalian immune system by siRNAs
Marques, J. T., & Williams, B. R. G. (2005) · Nature Biotechnology · doi:10.1038/nbt1161 · Cited by 357 · see citing works
Anderson, B. R., Muramatsu, H., Jha, B. K., Silverman, R. H., Weissman, D., & Kariko, K. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr586 · Cited by 356 · see citing works
Self-citationA comprehensive map of the toll‐like receptor signaling network
Oda, K., & Kitano, H. (2006) · Molecular Systems Biology · doi:10.1038/msb4100057 · Cited by 354 · see citing works
NKG2D function protects the host from tumor initiation
Smyth, M. J., Swann, J. B., Cretney, E., Zerafa, N., Yokoyama, W. M., & Hayakawa, Y. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050994 · Cited by 344 · see citing works
Three decades of messenger RNA vaccine development
Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H. (2019) · Nano Today · doi:10.1016/j.nantod.2019.100766 · Cited by 342 · see citing works
Schaefer, T. M., Desouza, K., Fahey, J. V., Beagley, K. W., & Wira, C. R. (2004) · Immunology · doi:10.1111/j.1365-2567.2004.01898.x · Cited by 341 · see citing works
Sensing of Viral Infection and Activation of Innate Immunity by Toll-Like Receptor 3
Vercammen, E., Staal, J., & Beyaert, R. (2008) · Clinical Microbiology Reviews · doi:10.1128/cmr.00022-07 · Cited by 322 · see citing works
Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment
Sato, Y., Goto, Y., Narita, N., & Hoon, D. S. �. (2009) · Cancer Microenvironment · doi:10.1007/s12307-009-0022-y · Cited by 317 · see citing works
Clearance of apoptotic and necrotic cells and its immunological consequences
Krysko, D. V., D’Herde, K., & Vandenabeele, P. (2006) · Apoptosis · doi:10.1007/s10495-006-9527-8 · Cited by 316 · see citing works
Kim, D., Kim, M. A., Cho, I., Kim, M. S., Lee, S., Jo, E., Choi, S., Park, K., Kim, J. S., Akira, S., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m607277200 · Cited by 315 · see citing works
Kreiter, S., Selmi, A., Diken, M., Koslowski, M., Britten, C. M., Huber, C., Türeci, Ö., & Sahin, U. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0699 · Cited by 309 · see citing works
Mollen, K. P., Anand, R., Tsung, A., Prince, J. M., Levy, R. M., & Billiar, T. R. (2006) · Shock · doi:10.1097/01.shk.0000228797.41044.08 · Cited by 306 · see citing works
Emerging role of Toll-like receptors in the control of pain and itch
Liu, T., Gao, Y., & Ji, R. (2012) · Neuroscience Bulletin · doi:10.1007/s12264-012-1219-5 · Cited by 302 · see citing works
The Multirole of Liposomes in Therapy and Prevention of Infectious Diseases
Nisini, R., Poerio, N., Mariotti, S., Santis, F. D., & Fraziano, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00155 · Cited by 299 · see citing works
Toll‐like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators
Bsibsi, M., Persoon-Deen, C., Verwer, R. W. H., Meeuwsen, S., Ravid, R., & van Noort, J. M. (2006) · Glia · doi:10.1002/glia.20328 · Cited by 296 · see citing works
DAMPs as mediators of sterile inflammation in aging-related pathologies
Feldman, N., Rotter-Maskowitz, A., & Okun, E. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.01.003 · Cited by 283 · see citing works
Li, L., Acioglu, C., Heary, R. F., & Elkabes, S. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.10.007 · Cited by 283 · see citing works
Karikó, K., Muramatsu, H., Keller, J. M., & Weissman, D. (2012) · Molecular Therapy · doi:10.1038/mt.2012.7 · Cited by 282 · see citing works
Self-citationRoelofs, M. F., Boelens, W. C., Joosten, L. A. B., Abdollahi‐Roodsaz, S., Geurts, J., Wunderink, L. U., Schreurs, B. W., van den Berg, W. B., & Radstake, T. R. D. J. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.11.7021 · Cited by 278 · see citing works
Innate Immune Recognition in Infectious and Noninfectious Diseases of the Lung
Opitz, B., van Laak, V., Eitel, J., & Suttorp, N. (2010) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200909-1427so · Cited by 274 · see citing works
The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines
Morais, P., Adachi, H., & Yu, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.789427 · Cited by 274 · see citing works
Lipid Nanoparticle-Delivered Chemically Modified mRNA Restores Chloride Secretion in Cystic Fibrosis
Robinson, E., MacDonald, K. D., Slaughter, K., McKinney, M., Patel, S., Sun, C., & Sahay, G. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.05.014 · Cited by 272 · see citing works
Differential Role for TLR3 in Respiratory Syncytial Virus-Induced Chemokine Expression
Rudd, B. D., Burstein, E., Duckett, C. S., Li, X., & Lukacs, N. W. (2005) · Journal of Virology · doi:10.1128/jvi.79.6.3350-3357.2005 · Cited by 271 · see citing works
Principles for designing an optimal mRNA lipid nanoparticle vaccine
Kon, E., Elia, U., & Peer, D. (2022) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2021.09.016 · Cited by 269 · see citing works
Schaefer, T. M., Fahey, J. V., Wright, J. A., & Wira, C. R. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.2.992 · Cited by 265 · see citing works
Challenges in developing personalized neoantigen cancer vaccines
Katsikis, P. D., Ishii, K. J., & Schliehe, C. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00937-y · Cited by 265 · see citing works
Inhibition of Toll-like Receptor and Cytokine Signaling—A Unifying Theme in Ischemic Tolerance
Karikó, K., Weissman, D., & Welsh, F. A. (2004) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000145666.68576.71 · Cited by 260 · see citing works
Self-citationde 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 260 · see citing works
Transcriptional signaling by double-stranded RNA: role of TLR3
Sen, G. C., & Sarkar, S. N. (2005) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2005.01.006 · Cited by 258 · see citing works
Preferential expression and function of Toll-like receptor 3 in human astrocytes
Farina, C., Krumbholz, M., Giese, T., Hartmann, G., Aloisi, F., & Meinl, E. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.09.009 · Cited by 252 · see citing works
Characterization of Toll-like receptors in the female reproductive tract in humans
Fazeli, A., Bruce, C., & Anumba, D. O. C. (2005) · Human Reproduction · doi:10.1093/humrep/deh775 · Cited by 246 · see citing works
Recent Advances in Lipid Nanoparticles and Their Safety Concerns for mRNA Delivery
Wang, J., Ding, Y., Chong, K. C., Cui, M., Cao, Z., Tang, C., Tian, Z., Hu, Y., Zhao, Y., & Jiang, S. (2024) · Vaccines · doi:10.3390/vaccines12101148 · Cited by 246 · see citing works
Garg, A. D., Dudek-Perić, A. M., Romano, E., & Agostinis, P. (2015) · The International Journal of Developmental Biology · doi:10.1387/ijdb.150061pa · Cited by 244 · see citing works
Inflammation and immune surveillance in cancer
Chow, M. T., Möller, A., & Smyth, M. J. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.12.004 · Cited by 241 · see citing works
The role of Toll-like receptors in the host response to viruses
Bowie, A., & Haga, I. R. (2005) · Molecular Immunology · doi:10.1016/j.molimm.2004.11.007 · Cited by 239 · see citing works
ROLE OF TOLL-LIKE RECEPTORS IN THE DEVELOPMENT OF SEPSIS
Tsujimoto, H., Ono, S., Efron, P. A., Scumpia, P. O., Moldawer, L. L., & Mochizuki, H. (2008) · Shock · doi:10.1097/shk.0b013e318157ee55 · Cited by 239 · see citing works
Toll-Like Receptor 3 Is a Potent Negative Regulator of Axonal Growth in Mammals
Cameron, J. S., Alexopoulou, L., Sloane, J. A., DiBernardo, A., Ma, Y., Kosaras, B., Flavell, R. A., Strittmatter, S. M., Volpe, J. J., Sidman, R. L., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4290-06.2007 · Cited by 235 · see citing works
mRNA as gene therapeutic: How to control protein expression
Tavernier, G., Andries, O., Demeester, J., Sanders, N. N., De Smedt, S. C., & Rejman, J. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.10.020 · Cited by 232 · see citing works
Strategies to reduce the risks of mRNA drug and vaccine toxicity
Bitounis, D., Jacquinet, E., Rogers, M. A., & Amiji, M. M. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00859-3 · Cited by 237 · see citing works
Danger signalling during cancer cell death: origins, plasticity and regulation
Garg, A. D., Martin, S., Gołąb, J., & Agostinis, P. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.48 · Cited by 225 · see citing works
Cassatella, M. A., Mosna, F., Micheletti, A., Lisi, V., Tamassia, N., Cont, C., Calzetti, F., Pelletier, M., Pizzolo, G., & Krampera, M. (2011) · Stem Cells · doi:10.1002/stem.651 · Cited by 222 · see citing works
Mammalian Toll-like receptors: to immunity and beyond
Hopkins, P. A., & Sriskandan, S. (2005) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02801.x · Cited by 220 · see citing works
mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo
Rybakova, Y., Kowalski, P. S., Huang, Y., Gonzalez, J. T., Heartlein, M. W., DeRosa, F., Delcassian, D., & Anderson, D. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.05.012 · Cited by 218 · see citing works
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 215 · see citing works
Ioannidis, I., Ye, F., McNally, B. A., Willette, M., & Flaño, E. (2013) · Journal of Virology · doi:10.1128/jvi.01956-12 · Cited by 216 · see citing works
Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword
Dajon, M., Iribarren, K., & Cremer, I. (2016) · Immunobiology · doi:10.1016/j.imbio.2016.06.009 · Cited by 211 · see citing works
Preclinical Evaluation of TriMix and Antigen mRNA-Based Antitumor Therapy
Lint, S. V., Goyvaerts, C., Maenhout, S. K., Goethals, L., Disy, A., Benteyn, D., Pen, J. J., Bonehill, A., Heirman, C., Breckpot, K., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-2957 · Cited by 210 · see citing works
- Authors
- Karikó, K., Ni, H., Capodici, J., Lamphier, M., & Weissman, D.
- Affiliations
- University of Pennsylvania (US)
- Eisai (United States) (US)
- Corresponding author
- Karikó, Katalin
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-03
- Volume
- 279
- Issue
- 13
- Pages
- 12542-12550
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1986178107
- Cited by
- 1,062
- References
- 63
- Citations by year
- 2026: 19 · 2025: 41 · 2024: 39 · 2023: 64 · 2022: 48 · 2021: 55 · 2020: 37 · 2019: 32 · 2018: 41 · 2017: 51 · 2016: 38 · 2015: 46 · 2014: 46 · 2013: 57 · 2012: 67
- FWCI
- 19.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hl062060-05)
- National Heart, Lung, and Blood Institute (HL62060-04)
- National Institute of Allergy and Infectious Diseases (AI-50484, R01AI050484)
- 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 › interferon and immune responses
- Keywords
- TLR3, mRNA, endogenous ligands, innate immunity, dendritic cell maturation, necrotic cells, double-stranded RNA, interferon-alpha, NF-κB, tyrosine phosphorylation, IRF1, TNF-α, RNA secondary structure
- MeSH terms
- Cell Line, Dendritic Cells, Dose-Response Relationship, Drug, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Humans, Ligands, Luciferases, Membrane Glycoproteins, Necrosis, Nucleic Acid Conformation, Plasmids, Protein Kinases, Receptors, Cell Surface, RNA, RNA, Double-Stranded, RNA, Messenger, Transcription, Genetic, Transfection, Tumor Necrosis Factor-alpha, Tyrosine, Blotting, Northern, Signal Transduction, Up-Regulation, Interleukin-8, NF-kappa B, Staurosporine, Genistein, Toll-Like Receptors, Toll-Like Receptor 3, Interleukin-1 Receptor-Associated Kinases
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