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

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.

TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis

“…33,34 Furthermore, a mouse model of psoriasis is also deficient in epidermal Jun proteins. 35 In view of these supporting evidence, it will be worth to examine the expression or activity of TAK1 in human psoriatic skin biopsies.…”

Psoriasis — A possible candidate for vaccination

“…SLC9ARI is concerned with transport of ions across cell membranes and immune synapse formation in T cells and is adjacent to a putative binding site for the transcription factor RUNXI. It has also been proposed that Jun proteins, the genes for which are located at the 19p locus, may be implicated in psoriasis (Zenz et al 2005). Abrogation of Jun proteins has been shown to induce the production of cytokines and chemokines, which results in proliferation of keratinocytes and infiltration of the epidermis with inflammatory cells.…”

Le psoriasis : évolution et révolution

“…Cette production est beaucoup plus importante dans les fibroblastes psoriasiques que dans les fibroblastes normaux [6], ce qui permet de comprendre le lien entre les anomalies cutanées et l'activation des cellules inflammatoires. Deux publications récentes permettent de quitter la mode du psoriasis comme maladie auto-immune liée à une anomalie du lymphocyte T [7,8] : portant sur l'étude de deux modèles animaux très proches du psoriasis humain, et résultant d'anomalies principalement [7] ou uniquement [8] cutanées, ces travaux permettent d'envisager de nouveau le psoriasis comme une maladie cutanée provoquée par une réponse excessive des cellules cutanées et inflammatoires aux agressions. La destruction sélective, dans une plaque de psoriasis, de la microcirculation du derme superficiel par laser pulsé à colorant est un traitement efficace.…”