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.

  • Letter
  • Published:

Dynamic expression of epidermal caspase 8 simulates a wound healing response

Nature volume 458, pages 519–523 (2009)Cite this article

Abstract

Tissue homeostasis and regeneration are regulated by an intricate balance of seemingly competing processes—proliferation versus differentiation, and cell death versus survival1. Here we demonstrate that the loss of epidermal caspase 8, an important mediator of apoptosis2, recapitulates several phases of a wound healing response in the mouse. The epidermal hyperplasia in the caspase 8 null skin is the culmination of signals exchanged between epidermal keratinocytes, dermal fibroblasts and leukocytic cells. This reciprocal interaction is initiated by the paracrine signalling of interleukin 1α (IL1α), which activates both skin stem cell proliferation and cutaneous inflammation. The non-canonical secretion of IL1α is induced by a p38-MAPK-mediated upregulation of NALP3 (also known as NLRP3), leading to inflammasome assembly and caspase 1 activation. Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1α-dependent NFκB signalling. Altogether, our findings illustrate how the loss of caspase 8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Effect of caspase 8 downregulation in the epidermis.
Figure 2: Characterization of the inflammatory response in the caspase 8 knockout skin.
Figure 3: Control of keratinocyte proliferation through epithelial–mesenchymal interactions.
Figure 4: Regulation of IL1α secretion.

Similar content being viewed by others

References

  1. Alonso, L. & Fuchs, E. Stem cells of the skin epithelium. Proc. Natl Acad. Sci. USA 100 (Suppl. 1). 11830–11835 (2003)

    Article  ADS  CAS  Google Scholar 

  2. Raj, D., Brash, D. E. & Grossman, D. Keratinocyte apoptosis in epidermal development and disease. J. Invest. Dermatol. 126, 243–257 (2006)

    Article  CAS  Google Scholar 

  3. Vasioukhin, V., Degenstein, L., Wise, B. & Fuchs, E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl Acad. Sci. USA 96, 8551–8556 (1999)

    Article  ADS  CAS  Google Scholar 

  4. Beisner, D. R., Ch’en, I. L., Kolla, R. V., Hoffmann, A. & Hedrick, S. M. Cutting edge: innate immunity conferred by B cells is regulated by caspase-8. J. Immunol. 175, 3469–3473 (2005)

    Article  CAS  Google Scholar 

  5. Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 11, 1351–1354 (2005)

    Article  CAS  Google Scholar 

  6. Levy, V., Lindon, C., Harfe, B. D. & Morgan, B. A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9, 855–861 (2005)

    Article  CAS  Google Scholar 

  7. Cotsarelis, G. Epithelial stem cells: a folliculocentric view. J. Invest. Dermatol. 126, 1459–1468 (2006)

    Article  CAS  Google Scholar 

  8. Martin, P. & Leibovich, S. J. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 15, 599–607 (2005)

    Article  CAS  Google Scholar 

  9. Jameson, J. & Havran, W. L. Skin γδ T-cell functions in homeostasis and wound healing. Immunol. Rev. 215, 114–122 (2007)

    Article  CAS  Google Scholar 

  10. Ichinohe, M. et al. Lack of phospholipase C-δ1 induces skin inflammation. Biochem. Biophys. Res. Commun. 356, 912–918 (2007)

    Article  CAS  Google Scholar 

  11. Perez-Moreno, M. et al. p120-catenin mediates inflammatory responses in the skin. Cell 124, 631–644 (2006)

    Article  CAS  Google Scholar 

  12. Hobbs, R. M. & Watt, F. M. Regulation of interleukin-1α expression by integrins and epidermal growth factor receptor in keratinocytes from a mouse model of inflammatory skin disease. J. Biol. Chem. 278, 19798–19807 (2003)

    Article  CAS  Google Scholar 

  13. Hobbs, R. M., Silva-Vargas, V., Groves, R. & Watt, F. M. Expression of activated MEK1 in differentiating epidermal cells is sufficient to generate hyperproliferative and inflammatory skin lesions. J. Invest. Dermatol. 123, 503–515 (2004)

    Article  CAS  Google Scholar 

  14. Murphy, J. E., Morales, R. E., Scott, J. & Kupper, T. S. IL-1α, innate immunity, and skin carcinogenesis: the effect of constitutive expression of IL-1α in epidermis on chemical carcinogenesis. J. Immunol. 170, 5697–5703 (2003)

    Article  CAS  Google Scholar 

  15. Werner, S. & Smola, H. Paracrine regulation of keratinocyte proliferation and differentiation. Trends Cell Biol. 11, 143–146 (2001)

    Article  CAS  Google Scholar 

  16. Hauser, C., Saurat, J. H., Schmitt, A., Jaunin, F. & Dayer, J. M. Interleukin 1 is present in normal human epidermis. J. Immunol. 136, 3317–3323 (1986)

    CAS  PubMed  Google Scholar 

  17. Kaufman, C. K. & Fuchs, E. It’s got you covered. NF-κB in the epidermis. J. Cell Biol. 149, 999–1004 (2000)

    Article  CAS  Google Scholar 

  18. Murphy, J. E., Robert, C. & Kupper, T. S. Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity. J. Invest. Dermatol. 114, 602–608 (2000)

    Article  CAS  Google Scholar 

  19. Yamanaka, K. et al. Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18. J. Immunol. 165, 997–1003 (2000)

    Article  CAS  Google Scholar 

  20. Groves, R. W., Mizutani, H., Kieffer, J. D. & Kupper, T. S. Inflammatory skin disease in transgenic mice that express high levels of interleukin 1α in basal epidermis. Proc. Natl Acad. Sci. USA 92, 11874–11878 (1995)

    Article  ADS  CAS  Google Scholar 

  21. Faustin, B. & Reed, J. C. Sunburned skin activates inflammasomes. Trends Cell Biol. 18, 4–8 (2008)

    Article  CAS  Google Scholar 

  22. Feldmeyer, L. et al. The inflammasome mediates UVB-induced activation and secretion of interleukin-1β by keratinocytes. Curr. Biol. 17, 1140–1145 (2007)

    Article  CAS  Google Scholar 

  23. Johansen, C., Moeller, K., Kragballe, K. & Iversen, L. The activity of caspase-1 is increased in lesional psoriatic epidermis. J. Invest. Dermatol. 127, 2857–2864 (2007)

    Article  CAS  Google Scholar 

  24. Al-Mashat, H. A. et al. Diabetes enhances mRNA levels of proapoptotic genes and caspase activity, which contribute to impaired healing. Diabetes 55, 487–495 (2006)

    Article  CAS  Google Scholar 

  25. Chun, H. J. et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419, 395–399 (2002)

    Article  ADS  CAS  Google Scholar 

  26. Anderson, J. P. et al. Structural, expression, and evolutionary analysis of mouse CIAS1. Gene 338, 25–34 (2004)

    Article  CAS  Google Scholar 

  27. Hohl, D. et al. Characterization of human loricrin. Structure and function of a new class of epidermal cell envelope proteins. J. Biol. Chem. 266, 6626–6636 (1991)

    CAS  PubMed  Google Scholar 

  28. Aravalli, R. N., Hu, S., Rowen, T. N., Palmquist, J. M. & Lokensgard, J. R. Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to herpes simplex virus. J. Immunol. 175, 4189–4193 (2005)

    Article  CAS  Google Scholar 

  29. Kobielak, A. & Fuchs, E. Links between α-catenin, NF-κB, and squamous cell carcinoma in skin. Proc. Natl Acad. Sci. USA 103, 2322–2327 (2006)

    Article  ADS  CAS  Google Scholar 

  30. Li, J., Yin, H. L. & Yuan, J. Flightless-I regulates proinflammatory caspases by selectively modulating intracellular localization and caspase activity. J. Cell Biol. 181, 321–333 (2008)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Hedrick, W. Havran, B. Yu, D. Witherden, A. Hoffmann, D. Stachura and members of the Jamora laboratory for providing reagents and helpful discussions. This work was supported by grants from the National Institutes of Health (NIAMS grant number 5R01AR053185-03) and the American Skin Association, and a Career Award from the Dermatology Foundation.

Author Contributions P.L., D.L., C.C., S.C. and C.J. performed the experiments; I.C. engineered the caspase 8 floxed mice; P.L. and C.J. designed the experiments; P.L., D.L. and C.J. wrote the manuscript.

Author information

Authors and Affiliations

  1. Division of Biological Sciences, Section of Cell and Developmental Biology, Natural Science Building, Room 6311, 9500 Gilman Drive, MC 0380,

    Pedro Lee, Dai-Jen Lee, Carol Chan, Shih-Wei Chen & Colin Jamora

  2. Division of Biological Sciences, Section of Molecular Biology, Natural Science Building, Room 5116, 9500 Gilman Drive, MC 0377,

    Irene Ch’en

  3. Department of Medicine (Dermatology), Natural Science Building, Room 6113, 9500 Gilman Drive, MC 0380, La Jolla, California 92093, USA,

    Colin Jamora

Authors
  1. Pedro Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dai-Jen Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carol Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shih-Wei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Irene Ch’en
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Colin Jamora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Colin Jamora.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-9 with Legends and a Supplementary Reference (PDF 1274 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, P., Lee, DJ., Chan, C. et al. Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 458, 519–523 (2009). https://doi.org/10.1038/nature07687

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07687

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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