mRNA Is an Endogenous Ligand for Toll-like Receptor 3*

By K. Karikó, Houping Ni, John Capodici, M. Lamphier, D. Weissman. Journal of Biological Chemistry, 2004

1,061 citations recorded by the source corpus.

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-κB-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-κB 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-α, 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-α 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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/571f3d9a20eeb6c5802373b1409ab2472bbde485

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Citations in the corpus

Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. (2005, positive): “Double-stranded (ds)RNA, a RNAs including influenza, adeno, and herpes simplex; frequent viral constituent, has been shown to activate surprisingly, modified nucleosides were more frequent TLR3 (Alexopoulou et al., 2001; Wang et al., 2004), sin-in viral than in cellular mRNAs (Bokar and Rottman, gle”
Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. (2006, background): “Moreover, Hsp70, Hsp90, gp96 and calreticulin specifically released by necrotic cells [195], activate APCs, including DCs [196,203–205]. mRNA released from necrotic cells is a potent host-derived activator of TLR3, inducing the activation of NFκB and the expression of TNFα, IRF-1 and IL-1 receptor a”
The role of oxidative stress during inflammatory processes (2013, neutral): “, 2013) – mRNA: TLR3 (Kariko et al., 2004) – Small nuclear ribonucleoprotein particles (snRNPs): TLR7, TLR8 (Vollmer et al.”
Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury (2011, background): “, heat shock proteins [58], mRNA [59], degraded extracellular matrix (ECM) components [60]).”
Modified mRNA vaccines protect against Zika virus infection (2017, positive): “…that optimize translation efficiency and intracellular stability, and a proprietary nucleoside modification to minimize the indiscriminate activation of innate immunity. mRNA can stimulate innate immunity through Toll-like and RIG-I-like receptors (Desmet and Ishii, 2012; Kariko et al., 2004).”
Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens (2010, background): “…CD141+ DC was significantly enhanced by poly I:C. CD141+ DCs cross-present Ag from HCMV-infected necrotic cells Double stranded (ds) RNA released from dying cells and the dsRNA replication intermediary of many viruses are the natural ligands for TLR3 (Karikó et al., 2004; Cavassani et al., 2008).”
DAMPening Inflammation by Modulating TLR Signalling (2010, background): “One structure shows that TLR3 interacts with hydrophilic double-stranded RNA (dsRNA) via surfaceexposed sites [50].”
Immune activation in brain aging and neurodegeneration: too much or too little? (2009, background): “…by CNS trauma or disease (e.g., heat-shock proteins [HSPs], highmobility-group box protein 1 [HMGB1], fibrinogen, hypomethylated mammalian DNA, and RNA released from necrotic cells) (Kariko et al., 2004; Leadbetter et al., 2002; Ohashi et al., 2000; Smiley et al., 2001; Viglianti et al., 2003).”