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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 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]
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Metadata
- 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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