Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins.
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.
Zenz
Rainer
R
Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
Eferl
Robert
R
Kenner
Lukas
L
Florin
Lore
L
Hummerich
Lars
L
Mehic
Denis
D
Scheuch
Harald
H
Angel
Peter
P
Tschachler
Erwin
E
Wagner
Erwin F
EF
D000375:Aging / Q000502:physiology; D000818:Animals; D015535:Arthritis, Psoriatic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D004817:Epidermis / Q000378:metabolism*; D017353:Gene Deletion; D016758:Genes, jun / Q000235:genetics*; D006801:Humans; D051379:Mice; D010641:Phenotype; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D016755:Proto-Oncogene Proteins c-jun; D047888:Receptors, Tumor Necrosis Factor, Type I; D009418:S100 Proteins; D014409:Tumor Necrosis Factor-alpha