Third Party Funds Group - Sub project
Acronym: GRK 2599 FAIR P09
Start date : 01.01.2021
End date : 30.06.2025
Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects about 13% of children and 7% of adults in the United States (Fishbein et al., 2019)*. The etiology of AD is complex and poorly understood. Defects in skin barrier function, causing immune dysregulation, as well as genetic and environmental factors, were proposed to contribute to this disease (Czarnowicki et al., 2014*; Booth et al., 2017*). AD is associated with increased production of the alarmins thymic stromal lymphopoi-etin (TSLP) and IL-33 by keratinocytes and a Th2-biased immune response with eosinophilia and high levels of IL-4, IL-13 and IgE. A commonly used mouse model for AD is based on topical appli-cation of MC903, a Vitamin D3 analogon, to the ear skin, which elicits a strong ear swelling response (Moosbrugger-Martinz et al., 2017*).
We could previously show that mice with a genetic deletion of TSLP or its receptor (TSLPR) develop an ameliorated ear swelling response upon MC903 treatment (Schwartz et al., 2016). By analyzing mixed bone marrow (BM) chimeras generated with BM from DC-deficient mice (Ohnmacht et al., 2009), wild-type mice (C57BL/6) or TSLPR-deficient mice we further demonstrated that expression of TSLPR on DCs plays a critical role for the onset of skin inflammation (Schwartz et al., 2016). Hence, the phenotypic and functional characterization of TSLP- or IL-33 activated DCs will be the focus of aim 1 of the project.
We further observed that ear swelling and inflammation are much more pronounced after secondary MC903 treatment, which is reminiscent of a memory immune response. Interestingly, this memory response was dependent on CD8+ T cells and also occurred in the opposite, previously untreated ear (unpublished data). Therefore, we will follow up on this result as outlined in Aim 2 of the project.