Identification and characterization of pruritus pathways in chronic skin inflammation

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Identification and characterization of pruritus pathways in chronic skin inflammation: microbes as exogenous drivers of itchChronic pruritus is a major clinical complaint, has a high prevalence, severely reduces the quality of life and is difficult to treat. The main problem for the development of targeted therapies has been a lack of pathophysiologic concepts. The key objective of project #5 is the in-depth characterization of known (IL-31/IL-31RA) and the identification of novel pruritus pathways during chronic skin inflammation. We are investigating distinct skin diseases such as lichen planus (TH1), atopic dermatitis (TH2) and psoriasis (TH17) as “role models” of itch. During the first funding period, the applicants succeeded in recruiting atopic dermatitis, psoriasis and lichen planus patients as well as matching controls (total n=171) for a physical biomaterial collection. All individuals were clinically characterized, electrically stimulated and biomaterial (skin, PBMCs, plasma) was obtained further analyses. At this point, we identified a transcriptomic “pruritus signature” in atopic dermatitis patients. Furthermore, we defined IL-31-producing circulating cells as a subset of CLA+ CRTH2+ CCR4+ TH2 cells that belong to the effector memory population and demonstrated that IL-31 promotes the differentiation of plasmablasts in vivo. Moreover, we uncovered that basophils express TRPV1 and produce TSLP following IL-31 stimulation. In atopic dermatitis patients, we showed that the brain derived neurotrophic factor (BDNF) is released by eosinophils and induces neuronal growth. During the second funding period, the applicants will address the following aims: (1) Deep phenotyping of IL-31-producing cells; (2) unravel the relative contribution of distinct IL-31RA+ cell types to mediate barrier dysfunction, inflammation, neuronal growth and pruritus; (3) define and validate pruritus pathways in distinct chronic inflammatory skin diseases and (4) unravel the role of microbes as exogenous triggers of itch. The applicants will follow a common experimental path with (a) explore own or public datasets using bioinformatics, (b) further investigation using in vitro-models and (c) confirmation and validation of these findings in vivo. Along this path, we have pre-analyzed large own and public datasets, have obtained a significant bio-resource during the 1st period and will obtain more information from longitudinal analyses of transcriptomes as well as microbiomes in patients. Moreover, we will use state-of-the-art conditional knockout (Il31ra) and reporter (Il31) mouse models. Taken together, findings of this study will increase our understanding of pruritus pathways with an emphasis on understanding the role of IL-31RA signaling as well as of microbes as exogenous triggers of itch. It will define and validate biomarkers for chronic pruritus that may serve as therapeutic targets.