Functional specialization of proinflammatory dendritic cells in psoriasis

• Applicant: Professor Dr. Knut Schäkel
• Subject Area: Dermatology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289757521

Psoriasis is a common chronic inflammatory skin disease in which dendritic cells (DC) are thought to orchestrate the pathogenic Th17/Th1-dominated immune response. Our studies demonstrate the functional specialization of slan (6-sulfo LacNAc+) DC as an important proinflammatory DC subtype in psoriasis. Previously, we identified slanDC and reported on their proinflammatory function. In the meanwhile slanDC have also been described in other chronic inflammatory diseases such as lupus erythematosus, Crohns disease and multiple sclerosis. Skin lesion from psoriasis patients contain increased numbers of activated slanDC expressing the key proinflammatory molecules TNF-a, IL-23 and iNOS. Complexes of autologous nucleic acids and the antimicrobial peptide LL37 (Cathelicidin) triggering Toll-like receptors (TLR) are regarded as important stimuli for cell activation in psoriasis. For slanDC we could demonstrate expression of TLR7/8 and a high sensitivity to stimulation with LL37-complexed autologous RNA as well as synthetic TLR7- as well as TLR8- ligands. Stimulated slanDC can produce higher levels of the proinflammatory cytokines IL-23, IL-12, IL-1b as well as TNF-a than other DC subsets or monocytes and induce strong Th17/Th1-dominated immune responses. Our goal is to answer questions regarding the role of DC in the immunopathogenesis of psoriasis. Questions: 1. What is the in vivo relevance of slanDC for inducing and maintaining psoriasis skin inflammation? 2. Which unknown molecular and functional mechanisms allow slanDC to regulate the inflammatory immune response in psoriasis? 3. What is the spatial and temporal microanatomic localization of slanDC during the development and maintenance of psoriasis plaques? For these studies we will employ mouse models with human skin and leukocyte transplants, will develop targeting strategies for the depletion of slanDC, analyze gene expression of slanDC from lesional skin and correlate these findings with the microanatomic distribution of slanDC in the skin. We are convinced that the proposed study program has the potential to significantly increase our understanding of the immunopathogenesis of psoriasis and to identify new targets for therapeutic intervention in psoriasis. As slanDC play a proinflammatory role in different Th17/Th1 dominated chronic inflammatory diseases, the results of the propose work is potentially of broad interest.

• DFG Programme: Research Grants