Psoriasis: Molecular targets of denervation and therapy

In this thesis global transcriptomic effects of denervation were analyzed in unique cases showing unilateral resolution of psoriasis occurred following surgical denervation (chapter 2). In our studies, we focused on the epidermis, as this forms the main innate defence barrier of the skin. We analysed global transcriptomic effects of surgical denervation in a murine psoriasiform model (chapter 3). Because the contribution of neuromediators to innate defence is mostly unknown, we investigated the effects of SP, CGRP, and VIP on the epidermal expression of TLR and host defence peptides in an ex vivo skin explant model (chapter 4). The molecular epidermal targets of recombinant IL-4 in ex vivo stimulated biopsies from psoriatic and healthy skin were investigated (chapter 5). Furthermore, the effect of the biologic ustekinumab (anti IL-12/IL-23) on epidermal molecular markers of innate defence in uninvolved skin of patients with psoriasis was investigated (chapter 6). The following main conclusions were drawn: Denervation affected genes involved in epidermal barrier function, and TLR function, as the inflammatory response to the TLR7 ligand imiquimod is prevented in denervated skin. Denervation inhibited cutaneous CGRP expression and prevented the enhanced expression of CGRP by imiquimod. Ex vivo stimulation of skin with GCRP results in enhanced expression of epidermal TLR9. Established treatments reach beyond the dermal infiltrate and also target keratinocytes: IL-4 and ustekinumab therapy increase GATA3, which is a transcription factor critical for epidermal homeostasis, and down-regulate NGF expression, which is linked to inflammatory conditions.

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