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Ultraviolet radiation damages self noncoding RNA and is detected by TLR3

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.

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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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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.

Corresponding author

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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