Article | Published:

Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury

Nature Medicine volume 15, pages 13771382 (2009) | Download Citation

Abstract

The normal microflora of the skin includes staphylococcal species that will induce inflammation when present below the dermis but are tolerated on the epidermal surface without initiating inflammation. Here we reveal a previously unknown mechanism by which a product of staphylococci inhibits skin inflammation. This inhibition is mediated by staphylococcal lipoteichoic acid (LTA) and acts selectively on keratinocytes triggered through Toll-like receptor 3(TLR3). We show that TLR3 activation is required for normal inflammation after injury and that keratinocytes require TLR3 to respond to RNA from damaged cells with the release of inflammatory cytokines. Staphylococcal LTA inhibits both inflammatory cytokine release from keratinocytes and inflammation triggered by injury through a TLR2-dependent mechanism. To our knowledge, these findings show for the first time that the skin epithelium requires TLR3 for normal inflammation after wounding and that the microflora can modulate specific cutaneous inflammatory responses.

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Acknowledgements

We thank A. Peschel for advice regarding blocking LTA activity by the antibody; E. Raz from the University of California–San Diego for providing a C57BL/6 Tlr3-deficient mouse breeding pair; V. Nizet and E. Tistiskov for helpful discussion; G. Cheng, B. Beutler, R. Modlin and E. Raz for critical reading and helpful advice; and D. Bird for histological sections. This work was supported by US National Institutes of Health grants R56AI083358, R01AR052728 and R01 AI052453 and a US Veterans Administration Merit Award to R.L.G. and US National Institutes of Health grants DC00129 and DC006279 to A.F.R.

Author information

Affiliations

  1. Division of Dermatology, Department of Medicine, University of California–San Diego, San Diego, California, USA.

    • Yuping Lai
    • , Anna Di Nardo
    • , Teruaki Nakatsuji
    • , Anna L Cogen
    • , Katherine A Radek
    • , Chun-Ming Huang
    •  & Richard L Gallo
  2. VA San Diego Healthcare System, San Diego, California, USA.

    • Yuping Lai
    • , Anna Di Nardo
    • , Teruaki Nakatsuji
    • , Anke Leichtle
    • , Anna L Cogen
    • , Katherine A Radek
    • , Chun-Ming Huang
    • , Allen F Ryan
    •  & Richard L Gallo
  3. Department of Surgery/Otolaryngology, University of California–San Diego, San Diego, California, USA.

    • Anke Leichtle
    •  & Allen F Ryan
  4. School of Life Science, East China Normal University, Shanghai, China.

    • Yan Yang
    •  & Zi-Rong Wu
  5. Howard Hughes Medical Institute, Department of Immunology and Department of Microbiology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.

    • Lora V Hooper
  6. Biochemical Pharmacology, Department of Chemistry, University of Konstanz, Konstanz, Germany.

    • Richard R Schmidt
    •  & Sonja von Aulock
  7. Department of Pediatrics, University of California–San Diego, La Jolla, California, USA.

    • Richard L Gallo

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Contributions

Y.L. and R.L.G. designed the experiments; Y.L. performed most of the experiments and analyzed data; A.D.N. helped in culture of bone-marrow-derived dendritic cells and preparation of UVB-irradiated apoptotic and necrotic cells; T.N. and A.L. helped with mouse experiments; Y.Y. and Z.-R.W. designed the LPS-induced inflammation model; A.L.C. helped to perform initial experiments; L.V.H. provided germ-free mouse ear and intestine samples; R.R.S. and S.v.A. provided synthetic LTAs; K.A.R. showed how to make mouse wound models; C.-M.H. helped to modify the protocol for animal study; A.F.R. provided Tlr2-deficient mice; Y. L. and R.L.G. wrote and prepared the manuscript.

Corresponding author

Correspondence to Richard L Gallo.

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    Supplementary Text and Figures

    Supplementary Figures 1–8 and Supplementary Methods

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DOI

https://doi.org/10.1038/nm.2062

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