Kurzfassung

Epithelial barrier organs, including the skin, the lung and the intestine are continuously exposed to a wide variety of environmental antigens comprising chemicals, food antigens and commensal bacteria but also pathogens. The challenge for the immune system lies in discriminating harmless from dangerous antigens and to induce appropriate tolerogenic or protective immune responses. Chronic immune-mediated inflammatory diseases (IMID) at these environmental interfaces like, for example, contact...Epithelial barrier organs, including the skin, the lung and the intestine are continuously exposed to a wide variety of environmental antigens comprising chemicals, food antigens and commensal bacteria but also pathogens. The challenge for the immune system lies in discriminating harmless from dangerous antigens and to induce appropriate tolerogenic or protective immune responses. Chronic immune-mediated inflammatory diseases (IMID) at these environmental interfaces like, for example, contact dermatitis, psoriasis, asthma and inflammatory bowel diseases are caused by the loss of tolerance to self- or innocuous foreign antigens. Myeloid antigen presenting cells (APC), including tissue-resident macrophages (MØ) and, in particular, dendritic cells (DC) are strategically positioned at barrier organs and have the unique capacity to balance immunity and tolerance. As such they are attractive targets for immunotherapeutic approaches to re-establish tolerance and thereby treat IMID. However, different MØ and DC subpopulations exhibit a high degree of functional specialization and plasticity in their ability to induce particular effector or regulatory T cell responses depending on the context and type of antigen/pathogen they encounter. Moreover, the molecular signals that enable MØ and DC to mediate immune tolerance and prevent excessive immune activation in IMID are still largely unknown.
Recently published together with our own preparatory data strongly suggest that E-cadherin/β-catenin mediated cell adhesion and signaling are key regulators of MØ and DC function in vivo by coordinating the production of pro- and anti-inflammatory cytokines. To what extent E-cadherin and/or β-catenin signals modulate MØ/DC function in the steady state and during IMID at environmental barriers remains largely elusive. Thus, the overall aim of this research proposal is to unravel the underlying mechanisms by which the E-cadherin/β-catenin pathway governs the regulatory function of CD11c+ APC and, for the first time, different APC subsets at epithelial interfaces in the steady state and during IMID. To this aim, we will take advantage of a unique collection of cell type-specific knockout and transgenic mice generated in our laboratory with deficient E-cadherin/β-catenin or constitutively active β-catenin signaling, respectively. Specifically, we will focus our analysis on mouse models of selected IMID affecting the skin (dermatitis, psoriasis), the lung (asthma) and the intestine (colitis). Beyond an increased understanding of the molecular control of myeloid APC subpopulations by E-cadherin/β-catenin signals, this project will lead to the identification of novel targets to design improved therapeutic strategies for the treatment of human IMID.» weiterlesen» einklappen