Generation of Inducible Dermal Dendritic Cell Knockout/Reporter Mice

Yale University, New Haven CT

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Abstract

Psoriasis, affecting about 2% of the population, is one of the most common, yet enigmatic human skin disorders. Although the clinical manifestations of this disease are well characterized, the etiology and the pathogenesis of psoriasis remain largely unknown. General consensus supports that psoriasis is a CD4 T cell-mediated disease. However, exactly how autoreactive CD4 T cells are generated and how they mediate disease is unknown. In this regard, it is critical to understanding the contributions of various antigenpresenting cells in the initiation and maintenance of this disease. Psoriatic lesions are often accompanied by clusters of CD4 T cells and dendritic cells (DCs) in the dermis beneath the affected epidermis. Here, we hypothesize that DCs in the dermis plays a key role in the initiation and maintenance of skin-reactive T cells contributing to psoriasis. To test this hypothesis, we propose to generate inducible dermal dendritic cell (DDC) knockout (KO)/reporter mice using the BAG Tg technology, utilizing resources in Core B (Generation and Preservation of Novel Mouse Models). Such mice will allow visualization of DDCs by intravital microscopy at the psoriatic skin (using Core C, In Vivo Imaging), and enable examination of the requirement of DDCs during the inductive and/or maintenance phases of psoriatic diseases. Several transgenic (Tg) mouse models in which cytokines or growth factors are expressed under the control of skin-specific promoters exhibit certain aspects of psoriasis and have been used to interrogate its pathogenic cascade. The DDC-KO/reporter mice will be crossed to the existing Tg models of psoriasis, and the initiation and maintenance of disease will be critically assessed. Collectively, these studies will provide fundamental insights into the mechanism of the pathogenesis of psoriasis by analyzing the involvement of DDCs in the initiation, maintenance and possibly regulation of psoriasis in vivo.