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Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3

Abstract

Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses1,2. Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication3. Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-κB and the production of type I interferons (IFNs). TLR3-deficient (TLR3-/-) mice showed reduced responses to polyinosine–polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines. MyD88 is an adaptor protein that is shared by all the known TLRs1. When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88. Moreover, poly(I:C) can induce activation of NF-κB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature.

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Figure 1: TLR3 specifically signals for NF-κB activation in response to poly(I:C).
Figure 2: Amino-acid sequence and expression pattern of TLR3, and generation of TLR3-/- mice.
Figure 3: Impaired responses to poly(I:C) from TLR3-/- cells.
Figure 4: Measurement of poly(I:C)-induced shock in TLR3-/- mice.
Figure 5: Responses to poly(I:C) in MyD88-/- and TLR3-transfected 293T cells.
Figure 6: Cellular responses independent of MyD88.

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Acknowledgements

We thank M. Nibert for providing viral dsRNA; S. Akira for providing the TLR2-/- and MyD88-/-mice; L. Evangelisti, D. Butkus, C. Hughes and J. Stein for technical assistance; and F. Manzo for secretarial work. This work was supported by the Howard Hughes Medical Institute and grants from the National Institutes of Health (NIH). L.A. was the recipient of a Human Frontier Science Program Postdoctoral Fellowship. R.M. is a Searle Scholar, R.A.F. is an Investigator and R.M. is an Assistant Investigator of the Howard Hughes Medical Institute.

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Correspondence to Ruslan Medzhitov or Richard A. Flavell.

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Alexopoulou, L., Holt, A., Medzhitov, R. et al. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001). https://doi.org/10.1038/35099560

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