iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://doi.org/10.1038/nature06116
Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide | Nature
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Nature volume 449, pages 564–569 (2007)Cite this article

Abstract

Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: LL37 is the key trigger of pDC activation in psoriatic skin.
Figure 2: LL37 converts self-DNA into a potent trigger of pDCs by forming aggregated and condensed structures.
Figure 3: Self-DNA coupled with LL37 is translocated into pDCs and activates them through TLR9.
Figure 4: LL37 retains DNA in early endocytic compartments of pDCs.

Similar content being viewed by others

References

  1. Liu, Y. J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005)

    Article  CAS  PubMed  Google Scholar 

  2. Colonna, M., Trinchieri, G. & Liu, Y. J. Plasmacytoid dendritic cells in immunity. Nature Immunol. 5, 1219–1226 (2004)

    Article  CAS  Google Scholar 

  3. Kadowaki, N. et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194, 863–869 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190–198 (2004)

    Article  CAS  Google Scholar 

  5. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004)

    Article  CAS  PubMed  ADS  Google Scholar 

  6. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)

    Article  CAS  PubMed  ADS  Google Scholar 

  7. Honda, K. et al. Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005)

    Article  CAS  PubMed  ADS  Google Scholar 

  8. Krieg, A. M. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20, 709–760 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006)

    Article  CAS  PubMed  Google Scholar 

  10. Stacey, K. J. et al. The molecular basis for the lack of immunostimulatory activity of vertebrate DNA. J. Immunol. 170, 3614–3620 (2003)

    Article  CAS  PubMed  Google Scholar 

  11. Barton, G. M., Kagan, J. C. & Medzhitov, R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nature Immunol. 7, 49–56 (2006)

    Article  CAS  Google Scholar 

  12. Yasuda, K. et al. Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and -independent pathways. J. Immunol. 174, 6129–6136 (2005)

    Article  CAS  PubMed  Google Scholar 

  13. Ronnblom, L., Eloranta, M. L. & Alm, G. V. Role of natural interferon-α producing cells (plasmacytoid dendritic cells) in autoimmunity. Autoimmunity 36, 463–472 (2003)

    Article  PubMed  CAS  Google Scholar 

  14. Barrat, F. J. et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202, 1131–1139 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Means, T. K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Theofilopoulos, A. N., Baccala, R., Beutler, B. & Kono, D. H. Type I interferons (α/β) in immunity and autoimmunity. Annu. Rev. Immunol. 23, 307–336 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. Blanco, P., Palucka, A. K., Gill, M., Pascual, V. & Banchereau, J. Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 294, 1540–1543 (2001)

    Article  CAS  PubMed  ADS  Google Scholar 

  18. Lowes, M. A., Bowcock, A. M. & Krueger, J. G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007)

    Article  CAS  PubMed  ADS  Google Scholar 

  19. Griffiths, C. E. & Voorhees, J. J. Psoriasis, T cells and autoimmunity. J. R. Soc. Med. 89, 315–319 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nickoloff, B. J. & Nestle, F. O. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J. Clin. Invest. 113, 1664–1675 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135–143 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kupper, T. S. & Fuhlbrigge, R. C. Immune surveillance in the skin: mechanisms and clinical consequences. Nature Rev. Immunol. 4, 211–222 (2004)

    Article  CAS  Google Scholar 

  23. Harder, J. & Schroder, J. M. Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins. J. Leukoc. Biol. 77, 476–486 (2005)

    Article  CAS  PubMed  Google Scholar 

  24. Glaser, R. et al. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nature Immunol. 6, 57–64 (2005)

    Article  CAS  Google Scholar 

  25. Zanetti, M. Cathelicidins, multifunctional peptides of the innate immunity. J. Leukoc. Biol. 75, 39–48 (2004)

    Article  PubMed  CAS  Google Scholar 

  26. Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002)

    Article  CAS  PubMed  ADS  Google Scholar 

  27. Braff, M. H., Bardan, A., Nizet, V. & Gallo, R. L. Cutaneous defense mechanisms by antimicrobial peptides. J. Invest. Dermatol. 125, 9–13 (2005)

    Article  CAS  PubMed  Google Scholar 

  28. Ong, P. Y. et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160 (2002)

    Article  CAS  PubMed  Google Scholar 

  29. Dufourcq, J., Neri, W. & Henry-Toulme, N. Molecular assembling of DNA with amphipathic peptides. FEBS Lett. 421, 7–11 (1998)

    Article  CAS  PubMed  Google Scholar 

  30. Niidome, T., Wakamatsu, M., Wada, A., Hirayama, T. & Aoyagi, H. Required structure of cationic peptide for oligonucleotide-binding and -delivering into cells. J. Pept. Sci. 6, 271–279 (2000)

    Article  CAS  PubMed  Google Scholar 

  31. Kubo, T. & Fujii, M. Specific binding and stabilization of DNA and phosphorothioate DNA by amphiphilic α-helical peptides. Nucleosides Nucleotides Nucleic Acids 20, 1313–1316 (2001)

    Article  CAS  PubMed  Google Scholar 

  32. Sandgren, S. et al. The human antimicrobial peptide LL-37 transfers extracellular DNA plasmid to the nuclear compartment of mammalian cells via lipid rafts and proteoglycan-dependent endocytosis. J. Biol. Chem. 279, 17951–17956 (2004)

    Article  CAS  PubMed  Google Scholar 

  33. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000)

    Article  CAS  PubMed  ADS  Google Scholar 

  34. Guiducci, C. et al. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J. Exp. Med. 203, 1999–2008 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Harder, J., Bartels, J., Christophers, E. & Schroder, J. M. A peptide antibiotic from human skin. Nature 387, 861 (1997)

    Article  CAS  PubMed  ADS  Google Scholar 

  36. Dorschner, R. A. et al. Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus . J. Invest. Dermatol. 117, 91–97 (2001)

    Article  CAS  PubMed  Google Scholar 

  37. Heilborn, J. D. et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J. Invest. Dermatol. 120, 379–389 (2003)

    Article  CAS  PubMed  Google Scholar 

  38. Frohm, M. et al. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem. 272, 15258–15263 (1997)

    Article  CAS  PubMed  Google Scholar 

  39. Schauber, J. et al. Heterogeneous expression of human cathelicidin hCAP18/LL-37 in inflammatory bowel diseases. Eur. J. Gastroenterol. Hepatol. 18, 615–621 (2006)

    Article  CAS  PubMed  Google Scholar 

  40. Paulsen, F. et al. Antimicrobial peptides are expressed and produced in healthy and inflamed human synovial membranes. J. Pathol. 198, 369–377 (2002)

    Article  CAS  PubMed  Google Scholar 

  41. Li, X., de Leeuw, E. & Lu, W. Total chemical synthesis of human psoriasin by native chemical ligation. Biochemistry 44, 14688–14694 (2005)

    Article  CAS  PubMed  Google Scholar 

  42. Zal, T., Zal, M. A., Lotz, C., Goergen, C. J. & Gascoigne, N. R. Spectral shift of fluorescent dye FM4-64 reveals distinct microenvironment of nuclear envelope in living cells. Traffic 7, 1607–1613 (2006)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank G. Lizee for critical reading of the manuscript; E. Wieder and K. Ramirez from the Flow Cytometry Core Facility for performing cell sorting; J. Wygant from the Monoclonal Antibodies Core Facility for generating the anti-LL37 monoclonal antibody; J. Bartels for ESI-MS analyses; and G. Reyes for technical assistance. This work was funded by a grant from the M. D. Anderson Cancer Foundation to M.G. Part of this work was supported by grants from the ‘Deutsche Forschungsgemeinschaft’ to J.-M.S. and to B.H.

Author Contributions R.L. performed and analysed most of the experiments in this study, and participated in their design. J.G. performed and analysed size-exclusion HPLC and helped in the atomic force microscopy experiments. V.F. and B.S. performed and analysed the experiments with transfected cell lines. B.C. and I.M. helped in establishing and analysing imaging experiments on endosomal trafficking. Yi-Hong Wang performed immunohistochemistry. B.H. collected and characterized clinical samples and participated in the expression analyses. W.C. generated the IRF7 construct. Yui-Hsi Wang helped in performing RT–PCR experiments. F.O.N. participated along with J.-M.S. and M.G. in the design of experiments with skin extracts. T.Z. helped in performing and evaluating imaging experiments using living cells. J.-M.S. designed, performed and evaluated the separation and biochemical analysis of skin extracts. Y.-J.L. provided critical suggestions and discussions throughout the study. M.G. conceived and supervised this study, was involved in the design and evaluation of all experiments, and wrote the manuscript with comments from co-authors.

Author information

Authors and Affiliations

  1. Department of Immunology, and,

    Roberto Lande, Josh Gregorio, Valeria Facchinetti, Yi-Hong Wang, Wei Cao, Yui-Hsi Wang, Bing Su, Tomasz Zal, Yong-Jun Liu & Michel Gilliet

  2. Department of Melanoma Medical Oncology, M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA,

    Michel Gilliet

  3. Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8002, USA,

    Bithi Chatterjee & Ira Mellman

  4. Genentech., 1 DNA Way, South San Francisco, California 94080, USA ,

    Bithi Chatterjee & Ira Mellman

  5. Department of Dermatology, Heinrich-Heine-University, Düsseldorf 40225, Germany,

    Bernhard Homey

  6. St John’s Institute of Dermatology, King’s College London School of Medicine, London SE1 9RT, UK

    Frank O. Nestle

  7. Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, University of Kiel, Kiel 24105, Germany

    Jens-Michael Schröder

Authors
  1. Roberto Lande
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josh Gregorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valeria Facchinetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bithi Chatterjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi-Hong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bernhard Homey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yui-Hsi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bing Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Frank O. Nestle
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tomasz Zal
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ira Mellman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jens-Michael Schröder
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yong-Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Michel Gilliet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel Gilliet.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

TITLE

This file contains Supplementary Figures S1-S7 and Legends. Figure S1 shows the identification of LL-37 in IFN-inducing HPLC fraction 26. Figure S2 shows the ability of genomic DNA of human and bacterial origin to induce IFN-α when coupled with LL-37. Figure S3 shows that the binding of LL-37 to DNA and the resulting structural changes in the DNA are reversible. Figure S4 shows internalization of LL-37 in the absence of DNA. Figure S5 shows that the ability of LL-37 to enhance DNA-mediated IFN-α requires the complex formation with the DNA. Figure S6 shows the preferential retention of LL-37-DNA in early endocytic compartments. Figure S7 shows the capacity of LL-37 to restore IFN-α induction by disrupted DNA aggregates. (PDF 1996 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lande, R., Gregorio, J., Facchinetti, V. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007). https://doi.org/10.1038/nature06116

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06116

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing