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Dynamic expression of epidermal caspase 8 simulates a wound healing response

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.

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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.

References

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

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  Google Scholar 

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

    CAS  Article  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)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  Google Scholar 

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

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  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)

    CAS  Article  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)

    ADS  CAS  Article  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)

    CAS  Article  Google Scholar 

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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.

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Correspondence to Colin Jamora.

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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

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