Immune networks triggered by cytokine thymic stromal lymphopoietin (TSLP) in the pathogenesis of atopic dermatitis – TSLPNetwork

The goal of this proposal is to obtain an integrated understanding of how skin TSLP-triggered immune responses are initiated and controlled, and to decipher and reconstruct the cellular and molecular networks in the inflamed tissue microenvironment. TSLP (thymic stromal lymphopoietin) is a cytokine expressed mainly in epithelial cells such as skin keratinocytes, and has emerged as a key player in the pathogenesis of allergic diseases including atopic dermatitis (AD, known also as eczema), asthma, allergic rhinitis and food allergy. The prevalence of these diseases has markedly increased over the last decades and represents an important health and financial burden. Even though our previous studies and those of others have established the role TSLP in the promotion of T helper type 2 (Th2) responses both in mouse and human, a thorough understanding of the immune cascade and network regulation driven by TSLP is still lacking. In this project, we will first focus on the crosstalk between dendritic cells (DCs), T cells and basophils in the TSLP-triggered immune response, particularly on Th2 priming, with the aim of elucidating the underlying molecular mechanisms. We will then extend our research to a comprehensive understanding of cellular and molecular interplay in TSLP-triggered immune networks using a systems biology approach. Furthermore, mechanisms and concepts will be explored in AD pathogenesis in the context of human skin allergic disorders and relevant mouse models. Finally, based on the acquired knowledge, we will explore new therapeutic tools interfering with the TSLP-triggered immune networks, in order to develop better therapy and prevention strategies for human allergic diseases.
The proposed studies will be performed along three axes by combining the expertise from three partners: 1) in vivo mechanistic studies using powerful mouse genetic tools and modeling systems (group of M. Li, IGBMC, Strasbourg); 2) in vitro human cell co-culture and ex vivo human skin explant culture systems (group of V. Soumelis, Institut Curie, Paris); and 3) human biopsy studies for clinical relevance (group of A. Taieb, CHU Bordeaux).
Overall, we expect to obtain a network view of how the cytokine TSLP drives immune responses, thus leading to a better understanding of the pathogenesis of AD and possibly other diseases related to dysregulation of TSLP, with the ultimate goal to develop innovative medical interventions. Innovative strategies developed in this project may be also used to study other pathogenic inflammatory networks in order to improve their understanding and therapeutic targeting.