Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins

  • A Corrigendum to this article was published on 30 March 2006

Abstract

Psoriasis is a frequent, inflammatory disease of skin and joints with considerable morbidity. Here we report that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB, a gene localized in the psoriasis susceptibility region PSORS6. Likewise, inducible epidermal deletion of JunB and its functional companion c-Jun in adult mice leads (within two weeks) to a phenotype resembling the histological and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions requires T and B cells and signalling through tumour necrosis factor receptor 1 (TNFR1). Prior to the disease onset, two chemotactic proteins (S100A8 and S100A9) previously mapped to the psoriasis susceptibility region PSORS4, are strongly induced in mutant keratinocytes in vivo and in vitro. We propose that the abrogation of JunB/activator protein 1 (AP-1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis thereby contributing to the phenotypic changes observed in psoriasis. Thus, these data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Reduced JunB expression in human psoriatic skin.
Figure 2: Inducible deletion of JunB and c- Jun in the epidermis of adult mice.
Figure 3: Mice lacking JunB and c- Jun in the epidermis exhibit the hallmarks of psoriasis.
Figure 4: Mice lacking JunB and c- Jun in the epidermis exhibit deregulated cytokine expression as observed in psoriasis.
Figure 5: Inducible deletion of JunB and c-Jun in Rag2 - and TNFR1 -deficient mice.

References

  1. 1

    Schon, M. P. Animal models of psoriasis—what can we learn from them? J. Invest. Dermatol. 112, 405–410 (1999)

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Shaulian, E. & Karin, M. AP-1 as a regulator of cell life and death. Nature Cell Biol. 4, E131–E136 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Eferl, R. & Wagner, E. F. AP-1: a double-edged sword in tumorigenesis. Nature Rev. Cancer 3, 859–868 (2003)

    CAS  Article  Google Scholar 

  5. 5

    Mehic, D., Bakiri, L., Ghannadan, M., Wagner, E. F. & Tschachler, E. Fos and jun proteins are specifically expressed during differentiation of human keratinocytes. J. Invest. Dermatol. 124, 212–220 (2005)

    CAS  Article  Google Scholar 

  6. 6

    Brocard, J. et al. Spatio-temporally controlled site-specific somatic mutagenesis in the mouse. Proc. Natl Acad. Sci. USA 94, 14559–14563 (1997)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Bonifati, C. & Ameglio, F. Cytokines in psoriasis. Int. J. Dermatol. 38, 241–251 (1999)

    CAS  Article  Google Scholar 

  8. 8

    Uyemura, K., Yamamura, M., Fivenson, D. F., Modlin, R. L. & Nickoloff, B. J. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J. Invest. Dermatol. 101, 701–705 (1993)

    CAS  Article  Google Scholar 

  9. 9

    Kong, J. & Li, Y. C. Upregulation of interleukin-18 expression in mouse primary keratinocytes induced to differentiate by calcium. Arch. Dermatol. Res. 294, 370–376 (2002)

    CAS  Article  Google Scholar 

  10. 10

    Lee, E. et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J. Exp. Med. 199, 125–130 (2004)

    CAS  Article  Google Scholar 

  11. 11

    Hashimoto, K. Regulation of keratinocyte function by growth factors. J. Dermatol. Sci. 24, S46–S50 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Schlingemann, J. et al. Profile of gene expression induced by the tumour promotor TPA in murine epithelial cells. Int. J. Cancer 104, 699–708 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Tanaka, T. S. et al. Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray. Proc. Natl Acad. Sci. USA 97, 9127–9132 (2000)

    ADS  Article  Google Scholar 

  14. 14

    Florin, L. et al. Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing. Oncogene 23, 7005–7017 (2004)

    CAS  Article  Google Scholar 

  15. 15

    VanBuren, V. et al. Assembly, verification and initial annotation of the NIA mouse 7.4K cDNA clone set. Genome Res. 12, 1999–2003 (2002)

    Article  Google Scholar 

  16. 16

    Broome, A. M., Ryan, D. & Eckert, R. L. S100 protein subcellular localization during epidermal differentiation and psoriasis. J. Histochem. Cytochem. 51, 675–685 (2003)

    CAS  Article  Google Scholar 

  17. 17

    Waseem, A. et al. Keratin 15 expression in stratified epithelia: downregulation in activated keratinocytes. J. Invest. Dermatol. 112, 362–369 (1999)

    CAS  Article  Google Scholar 

  18. 18

    Campbell, L. et al. Downregulation and altered spatial pattern of caveolin-1 in chronic plaque psoriasis. Br. J. Dermatol. 147, 701–709 (2002)

    CAS  Article  Google Scholar 

  19. 19

    Apte, S. S., Olsen, B. R. & Murphy, G. The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J. Biol. Chem. 270, 14313–14318 (1995)

    CAS  Article  Google Scholar 

  20. 20

    Black, R. A. TIMP3 checks inflammation. Nature Genet. 36, 934–935 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Nickoloff, B. J. et al. Is psoriasis a T-cell disease? Exp. Dermatol. 9, 359–375 (2000)

    CAS  Article  Google Scholar 

  22. 22

    Galadari, H., Fuchs, B. & Lebwohl, M. Newly available treatments for psoriatic arthritis and their impact on skin psoriasis. Int. J. Dermatol. 42, 231–237 (2003)

    Article  Google Scholar 

  23. 23

    Cook, P. W., Pittelkow, M. R. & Piepkorn, M. Overexpression of amphiregulin in the epidermis of transgenic mice induces a psoriasis-like cutaneous phenotype. J. Invest. Dermatol. 113, 860 (1999)

    CAS  Article  Google Scholar 

  24. 24

    Cheng, J. et al. Cachexia and graft-vs.-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice. Genes Dev. 6, 1444–1456 (1992)

    CAS  Article  Google Scholar 

  25. 25

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

    ADS  CAS  Article  Google Scholar 

  26. 26

    Carroll, J. M., Crompton, T., Seery, J. P. & Watt, F. M. Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss. J. Invest. Dermatol. 108, 412–422 (1997)

    CAS  Article  Google Scholar 

  27. 27

    Guo, L., Yu, Q. C. & Fuchs, E. Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice. EMBO J. 12, 973–986 (1993)

    CAS  Article  Google Scholar 

  28. 28

    Xia, Y. P. et al. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 102, 161–168 (2003)

    CAS  Article  Google Scholar 

  29. 29

    Li, A. G., Wang, D., Feng, X. H. & Wang, X. J. Latent TGFβ1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J. 23, 1770–1781 (2004)

    CAS  Article  Google Scholar 

  30. 30

    Sano, S. et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nature Med. 11, 43–49 (2005)

    ADS  CAS  Article  Google Scholar 

  31. 31

    Semprini, S. et al. Evidence for differential S100 gene over-expression in psoriatic patients from genetically heterogeneous pedigrees. Hum. Genet. 111, 310–313 (2002)

    CAS  Article  Google Scholar 

  32. 32

    Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. & Tessier, P. A. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J. Immunol. 170, 3233–3242 (2003)

    CAS  Article  Google Scholar 

  33. 33

    Vandal, K. et al. Blockade of S100A8 and S100A9 suppresses neutrophil migration in response to lipopolysaccharide. J. Immunol. 171, 2602–2609 (2003)

    CAS  Article  Google Scholar 

  34. 34

    Angel, P., Szabowski, A. & Schorpp-Kistner, M. Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene 20, 2413–2423 (2001)

    CAS  Article  Google Scholar 

  35. 35

    Johansen, C., Kragballe, K., Rasmussen, M., Dam, T. N. & Iversen, L. Activator protein 1 DNA binding activity is decreased in lesional psoriatic skin compared with nonlesional psoriatic skin. Br. J. Dermatol. 151, 600–607 (2004)

    CAS  Article  Google Scholar 

  36. 36

    Fang, D. et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nature Immunol. 3, 281–287 (2002)

    CAS  Article  Google Scholar 

  37. 37

    Gao, M. et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306, 271–275 (2004)

    ADS  CAS  Article  Google Scholar 

  38. 38

    Nickoloff, B. J. The search for pathogenic T cells and the genetic basis of psoriasis using a severe combined immunodeficient mouse model. Cutis 65, 110–114 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumour necrosis factor-alpha. J Exp Med 199, 731–736 (2004)

    CAS  Article  Google Scholar 

  40. 40

    Janco, R. L. & English, D. Cyclosporine and human neutrophil function. Transplantation 35, 501–503 (1983)

    CAS  Article  Google Scholar 

  41. 41

    Karashima, T., Hachisuka, H. & Sasai, Y. FK506 and cyclosporin A inhibit growth factor-stimulated human keratinocyte proliferation by blocking cells in the G0/G1 phases of the cell cycle. J. Dermatol. Sci. 12, 246–254 (1996)

    CAS  Article  Google Scholar 

  42. 42

    Elomaa, O. et al. Transgenic mouse models support HCR as an effector gene in the PSORS1 locus. Hum. Mol. Genet. 13, 1551–1561 (2004)

    CAS  Article  Google Scholar 

  43. 43

    Namazi, M. R. Paradoxical exacerbation of psoriasis in AIDS: proposed explanations including the potential roles of substance P and gram-negative bacteria. Autoimmunity 37, 67–71 (2004)

    CAS  Article  Google Scholar 

  44. 44

    Passegue, E. & Wagner, E. F. JunB suppresses cell proliferation by transcriptional activation of p16(INK4a) expression. EMBO J. 19, 2969–2979 (2000)

    CAS  Article  Google Scholar 

  45. 45

    Szabowski, A. et al. c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 103, 745–755 (2000)

    CAS  Article  Google Scholar 

  46. 46

    Passegue, E., Jochum, W., Schorpp-Kistner, M., Mohle-Steinlein, U. & Wagner, E. F. Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. Cell 104, 21–32 (2001)

    CAS  Article  Google Scholar 

  47. 47

    Passegue, E., Wagner, E. F. & Weissman, I. L. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119, 431–443 (2004)

    CAS  Article  Google Scholar 

  48. 48

    Kenner, L. et al. Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects. J. Cell Biol. 164, 613–623 (2004)

    CAS  Article  Google Scholar 

  49. 49

    Behrens, A. et al. Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J. 21, 1782–1790 (2002)

    CAS  Article  Google Scholar 

  50. 50

    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 

Download references

Acknowledgements

We are grateful to M. Sibilia, G. Stingl, D. Maurer, J. Smolen, G. Schett and A. Rot for critical comments and suggestions to the manuscript, M. Cotton for providing adeno-Cre viruses, H. Tkadletz for help in preparing the illustrations and J. Hess for support with S100 protein expression analyses. The IMP is funded by Boehringer Ingelheim and this work was supported by grants from the Austrian Research Foundation, the Deutsche Forschungsgemeinschaft and by the Research Training Network (RTN) Program of the European Community.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Erwin F. Wagner.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Figure S1

No psoriasis following single epidermal deletion of either JunB or c-Jun. (JPG 246 kb)

Supplementary Figure S2

Cytokine expression after 4 days following three Tam injections. (JPG 364 kb)

Supplementary Figure S3

Cytokine expression after 18 days following Tam injections. (JPG 111 kb)

Supplementary Figure S4

Induction of JunB/c-Jun deletion in the presence of ciprofloxacin. (JPG 1140 kb)

Supplementary Figures Legends

Text to accompany the above Supplementary Figures. (DOC 21 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zenz, R., Eferl, R., Kenner, L. et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437, 369–375 (2005). https://doi.org/10.1038/nature03963

Download citation

Further reading

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

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing