The inflammasome and skin diseases: biological and clinical aspects

- Background - Inflammatory diseases of the skin are highly prevalent in the general population. Genetic studies on monogenic and complex skin diseases have indicated that the innate immune system and barrier function of the skin contribute to their etiology and pathogenesis. Recent advances in the cell biology of inflammation, such as the discovery of Toll-like receptors (TLRs), NOD-like receptors (NLR) and the inflammasome as a multi-protein signalling/ effector platform, and the concept of auto-inflammatory disease, have provided arguments to consider a role for innate immune mechanisms in a number of skin disorders. Previous work of our groups has focused on the epidermal innate immune system in common skin diseases and clinical studies on the role of inflammasome-mediated signalling in Schnitzler syndrome, a rare auto-inflammatory disease. This project aims to study auto-inflammatory processes in human epidermis. Schnitzler syndrome will be used as a model because of the clear role of interleukin-1 (IL-1) in its pathogenesis. Results from experiments with Schnitzler syndrome will then prompt experiments in other, more common skin diseases. - Aims of the project - (1) Make an inventory of expressed genes of the TLR and NLR pathways in vivo, in normal and inflamed epidermis. (2) Investigate the inflammasome in cultured normal human keratinocytes. (3) Investigate inflammasome and IL-1beta signalling in primary keratinocytes, monocytes and macrophages from Schnitzler syndrome patients, compared to controls and patients with other inflammatory skin diseases. (4) Extend our clinical studies on Schnitzler syndrome. - Work plan - (1) A comprehensive gene expression analysis will be performed in purified epidermal cells from controls and patients with inflammatory skin diseases (Schnitzler's syndrome, psoriasis and atopic dermatitis). (2) In vitro, expression of these genes will be studied in normal cultured keratinocytes under various conditions of stimulation, such as TLR/NLR ligands and inflammatory cytokines. Analysis will be performed by qPCR, ELISA and fluorimetric bead analysis. IL-1beta gene induction, protein processing and secretion will be studied in detail. (3) Primary keratinocyte cultures of Schnitzler syndrome patients will be established for comparison with keratinocytes from controls and other inflammatory diseases (cell banks are already available). Keratinocytes, monocytes and monocyte-derived macrophages will be stimulated in vitro and analyzed as mentioned under part 2. This will allow us to study cell-autonomous differences in inflammasome function between patients and controls. (4) We will investigate the histopathology of skin from patients with Schnitzler syndrome, and the relation to similar diseases such as chronic idiopathic urticaria and cryopyrin-associated periodic syndromes. At the clinical level, these diseases will be compared as to disease development, progression and response to treatment. - Rationale and perspectives - The role of the inflammasome and autoinflammatory mechanisms in skin diseases is largely unexplored, and clearly of scientific and clinical relevance. The project bridges the expertise of the candidate and the interest in biology of skin inflammation by the host lab.