E-cadherin and β-catenin signaling in Langerhans cells and DC for the maintenance of immune homeostasis in the oral mucosa

• Applicant: Professor Dr. Björn Clausen
• Subject Area: Immunology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315501751

Epithelial barriers to the environment, like the skin, lung, and oral mucosa, are continuously exposed to harmless environmental antigens, pathogens, and maintain homeostasis with the commensal bacteria. Dendritic cells (DC), including Langerhans cells (LC) that are only found in the skin epidermis and the oral epithelium, are strategically positioned at these barrier organs and have the unique capacity to balance immunity and tolerance. During the first funding period, we established that E-cadherin/ β-catenin cell adhesion is essential for LC to acquire their typical dendritic morphology in the epidermis, without affecting their function. Moreover, β-catenin signaling controls the function of DC in the lungs and regulates the severity of an allergic asthma reaction. In the oral mucosa, microbial dysbiosis and chronic infection with e.g. Porphyromonas (P.) gingivalis cause gingivitis and periodontitis, which is characterized by progressive and irreversible destruction of the tooth-supporting tissues. LC are indispensable to maintain mucosal homeostasis and downregulate inflammation-driven loss of the tooth-bearing alveolar bone. Whether E-cadherin/ β-catenin in LC/DC are essential to maintain microbial and immune homeostasis in the oral mucosa remains unknown. Thus, the overall aim of this project is to decipher the role of E-cadherin/ β-catenin signaling in oral mucosal LC and DC in the steady-state and during inflammation. To this end, we will use the unique LC/DC-specific E-cadherin and β-catenin knockout mice as well as mice expressing stabilized, constitutively active β-catenin in LC/DC, generated in the previous funding period. Our preparatory data indicate that the lack of E-cadherin impairs LC morphology, development and/or migration in the oral mucosa. Although the total number of DC is not reduced, this leads to dysbiosis and triggers T cell infiltration and proinflammatory cytokine production. On the other hand, constitutively active β-catenin signaling in LC/DC results in more regulatory T cells in the oral mucosa. These unique findings warrant a detailed analysis of the E-cadherin and β-catenin pathways in LC/DC-mediated immune homeostasis in the oral mucosa in the steady-state and during infection/ inflammation. Specifically, we will investigate the composition of the oral microbiota and a mouse model of P. gingivalis induced periodontitis in these transgenic mice. Moreover, we will apply single-cell RNA sequencing to scrutinize the molecular pathways affected by E-cadherin/ β-catenin signals in oral mucosal LC/DC. The expected results will significantly further our understanding of the cellular and molecular networks driving oral dysbiosis and periodontal disease. This study will identify novel targets that may enable improved immuno-therapeutic strategies for the treatment of periodontitis.

• DFG Programme: Research Grants