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Ultraviolet radiation damages self noncoding RNA and is detected by TLR3

Nature Medicine volume 18, pages 1286–1290 (2012)Cite this article

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Abstract

Exposure to ultraviolet B (UVB) radiation from the sun can result in sunburn, premature aging and carcinogenesis, but the mechanism responsible for acute inflammation of the skin is not well understood. Here we show that RNA is released from keratinocytes after UVB exposure and that this stimulates production of the inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from nonirradiated keratinocytes and peripheral blood mononuclear cells (PBMCs). Whole-transcriptome sequencing revealed that UVB irradiation of keratinocytes induced alterations in the double-stranded domains of some noncoding RNAs. We found that this UVB-damaged RNA was sufficient to induce cytokine production from nonirradiated cells, as UVB irradiation of a purified noncoding RNA (U1 RNA) reproduced the same response as the one we observed to UVB-damaged keratinocytes. The responses to both UVB-damaged self-RNAs and UVB-damaged keratinocytes were dependent on Toll-like receptor 3 (TLR3) and Toll-like receptor adaptor molecule 1 (TRIF). In response to UVB exposure, Tlr3−/− mice did not upregulate TNF-α in the skin. Moreover, TLR3 was also necessary for UVB-radiation–induced immune suppression. These findings establish that UVB damage is detected by TLR3 and that self-RNA is a damage-associated molecular pattern that serves as an endogenous signal of solar injury.

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Figure 1: RNA from UVB-irradiated keratinocytes induces the production of inflammatory cytokines.
Figure 2: UVB damage to U1 RNA generates products that induce the production of TNF-α and IL-6.
Figure 3: UVB damage to U1 RNA induces inflammatory cytokine release by activating TLR3.
Figure 4: Recognition of UVB-irradiated RNA by TLR3 is necessary for the inflammatory response to UVB damage.

References

  1. Armstrong, B.K. & Kricker, A. The epidemiology of UV induced skin cancer. J. Photochem. Photobiol. B 63, 8–18 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. El Ghissassi, F. et al. A review of human carcinogens–part D: radiation. Lancet Oncol. 10, 751–752 (2009).

    Article  PubMed  Google Scholar 

  3. De Fabo, E.C. & Noonan, F.P. Mechanism of immune suppression by ultraviolet irradiation in vivo. I. Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology. J. Exp. Med. 158, 84–98 (1983).

    Article  CAS  PubMed  Google Scholar 

  4. Sontag, Y. et al. Cells with UV-specific DNA damage are present in murine lymph nodes after in vivo UV irradiation. J. Invest. Dermatol. 104, 734–738 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Setlow, R.B. The wavelengths in sunlight effective in producing skin cancer: a theoretical analysis. Proc. Natl. Acad. Sci. USA 71, 3363–3366 (1974).

    Article  CAS  PubMed  Google Scholar 

  6. Bender, K., Gottlicher, M., Whiteside, S., Rahmsdorf, H.J. & Herrlich, P. Sequential DNA damage-independent and -dependent activation of NF-κB by UV. EMBO J. 17, 5170–5181 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Devary, Y., Rosette, C., DiDonato, J.A. & Karin, M. NF-κB activation by ultraviolet light not dependent on a nuclear signal. Science 261, 1442–1445 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Walsh, L.J. Ultraviolet B irradiation of skin induces mast cell degranulation and release of tumour necrosis factor-α. Immunol. Cell Biol. 73, 226–233 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Chen, G. & Goeddel, D.V. TNF-R1 signaling: a beautiful pathway. Science 296, 1634–1635 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).

    Article  CAS  Google Scholar 

  11. Akira, S., Hirano, T., Taga, T. & Kishimoto, T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 4, 2860–2867 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Vincek, V., Kurimoto, I., Medema, J.P., Prieto, E. & Streilein, J.W. Tumor necrosis factor α polymorphism correlates with deleterious effects of ultraviolet B light on cutaneous immunity. Cancer Res. 53, 728–732 (1993).

    CAS  PubMed  Google Scholar 

  13. Vermeer, M. & Streilein, J.W. Ultraviolet B light-induced alterations in epidermal Langerhans cells are mediated in part by tumor necrosis factor-α. Photodermatol. Photoimmunol. Photomed. 7, 258–265 (1990).

    CAS  PubMed  Google Scholar 

  14. Schwarz, A. et al. Ultraviolet-B–induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-α in the formation of sunburn cells. J. Invest. Dermatol. 104, 922–927 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Alexopoulou, L., Holt, A.C., Medzhitov, R. & Flavell, R.A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Casciola-Rosen, L.A., Anhalt, G. & Rosen, A. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J. Exp. Med. 179, 1317–1330 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Hoffman, R.W. et al. U1 RNA induces innate immunity signaling. Arthritis Rheum. 50, 2891–2896 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Griswold, D.E. et al. Activation of the IL-1 gene in UV-irradiated mouse skin: association with inflammatory sequelae and pharmacologic intervention. J. Invest. Dermatol. 97, 1019–1023 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Kutsch, C.L., Norris, D.A. & Arend, W.P. Tumor necrosis factor-α induces interleukin-1 α and interleukin-1 receptor antagonist production by cultured human keratinocytes. J. Invest. Dermatol. 101, 79–85 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Wurtmann, E.J. & Wolin, S.L. RNA under attack: cellular handling of RNA damage. Crit. Rev. Biochem. Mol. Biol. 44, 34–49 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Norval, M., Simpson, T.J., Bardshiri, E. & Crosby, J. Quantification of urocanic acid isomers in human stratum corneum. Photodermatol. 6, 142–145 (1989).

    CAS  PubMed  Google Scholar 

  22. Gilchrest, B.A., Eller, M.S. & Yaar, M. Telomere-mediated effects on melanogenesis and skin aging. J. Investig. Dermatol. Symp. Proc. 14, 25–31 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Kosmadaki, M.G. & Gilchrest, B.A. The role of telomeres in skin aging/photoaging. Micron 35, 155–159 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Wei, Y.D., Rannug, U. & Rannug, A. UV-induced CYP1A1 gene expression in human cells is mediated by tryptophan. Chem. Biol. Interact. 118, 127–140 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Murphy, G.M., Dowd, P.M., Hudspith, B.N., Brostoff, J. & Greaves, M.W. Local increase in interleukin-1-like activity following UVB irradiation of human skin in vivo. Photodermatol. 6, 268–274 (1989).

    CAS  PubMed  Google Scholar 

  26. Clydesdale, G.J., Dandie, G.W. & Muller, H.K. Ultraviolet light induced injury: immunological and inflammatory effects. Immunol. Cell Biol. 79, 547–568 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Lai, Y. et al. Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury. Nat Med. 15, 1377–1382 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Head from The Scripps Research Institute DNA Core Facility for performing RNA-Seq. We thank B. Gilchrest (Boston University, Boston, MA) for telomere oligonucleotides and advice, J. Laskin for advice and helpful discussion and M. Karin (University of California, San Diego, San Diego, CA) for providing Il1r−/− mice and for helpful discussion. This work was supported by US National Institutes of Health (NIH) grants R01-AR052728, NIH R01-AI052453 and R01 AI0833358 and a Veterans Affairs Merit Award to R.L.G., NIH R01-AR056667 to B.D.Y., the US National Institute of Environmental Health Sciences (NIEHS) Training Grant ES007148 and the NIEHS Center Grant ES005022 supporting J.J.B., and the Department of Veterans Affairs, NIH AR48805 and the Lupus Research Institute to E.L.G.

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Authors and Affiliations

  1. Division of Dermatology, University of California, San Diego, San Diego, California, USA.,

    Jamie J Bernard, Christopher Cowing-Zitron, Teruaki Nakatsuji, Beda Muehleisen, Jun Muto, Andrew W Borkowski, Benjamin D Yu & Richard L. Gallo

  2. Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA

    Jamie J Bernard

  3. Miami Veterans Affairs Medical Center, Miami, Florida, USA

    Laisel Martinez & Eric L Greidinger

  4. Division of Rheumatology, University of Miami Miller School of Medicine, Miami, Florida, USA

    Eric L Greidinger

  5. Veterans Affairs San Diego Healthcare System, San Diego, California, USA

    Richard L. Gallo

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  1. Jamie J Bernard
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Contributions

J.J.B. performed most of the experiments, analyzed results and wrote the manuscript. T.N., J.M., B.M. and A.W.B. assisted with mouse experiments and reviewed the manuscript. C.C.-Z. and B.D.Y. analyzed RNA-Seq results and reviewed the manuscript. E.L.G. and L.M. provided reagents, helped with the design and interpretation of experiments involving U1 RNA and reviewed the manuscript. R.L.G. supervised and designed experiments and wrote and prepared the manuscript.

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Correspondence to Richard L. Gallo.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7, Supplementary Table 1 and Supplementary Methods (PDF 1141 kb)

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Bernard, J., Cowing-Zitron, C., Nakatsuji, T. et al. Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med 18, 1286–1290 (2012). https://doi.org/10.1038/nm.2861

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