E-cadherin and β-catenin signaling in dendritic cells for the maintenance of immune homeostasis in the oral mucosa
1 PhD project offered in the IPP summer call Molecular Biomedicine & Ageing
Scientific Background
The oral mucosa represents a barrier tissue to the environment where the balance of immunity and tolerance is vital, as it is constantly exposed to pathogens and harmless foreign antigens, including commensals. A breakdown of this balance leads to dysbiosis resulting in periodontitis, an infection-induced inflammatory disease characterized by irreversible destruction of the tooth-supporting tissues including loss of the underlying bone. Moreover, it is considered a risk factor for life-threatening conditions such as cardiovascular disease. Dendritic cells (DC), including Langerhans cells (LC), have the unique capacity to promote both tolerogenic and inflammatory immune responses. Hence, in order to design effective therapeutic strategies to treat periodontitis and reduce the risk of developing comorbidities, it is essential to understand how DC in the oral mucosa maintain immune homeostasis.
PhD project: E-cadherin and β-catenin signaling in dendritic cells for the maintenance of immune homeostasis in the oral mucosa
One pathway that plays a crucial role in DC homeostasis and tolerance induction is E-cadherin/β-catenin signaling. The cell adhesion molecule E-cadherin is only expressed by LC and we recently showed that it is involved in the 2-step process of their differentiation in the oral mucosa. Notably, to what extent E-cadherin/β-catenin signaling regulates LC/DC homeostasis and function in the oral mucosa is not known. In pilot experiments, we analyzed the oral mucosa of transgenic mice lacking E-cadherin in CD11c+ cells (CD11c-EcadDEL) and observed an altered LC subset distribution and a dramatically changed morphology with more rounded cell bodies and fewer dendrites compared to controls. In the proposed project a detailed in vivo and in vitro analysis of CD11c-EcadDEL and β-catenin deficient (CD11c-βcatDEL) mice will be performed. First, we will assess LC and DC homeostasis, activation and migration in the different oral tissues by high-dimensional flow cytometry as well as the impact of CD11c-specific E-cadherin or β-catenin deletion on other immune cell populations. Moreover, we detected oral dysbiosis in our CD11c-EcadDEL mice and therefore, a detailed taxonomic microbiota analysis will be performed in this project. Since persistent microbial dysbiosis results in inflammation and subsequently alveolar bone loss, we will analyze the oral tissues of CD11c-EcadDEL and CD11c-βcatDEL mice for T cell infiltration and inflammatory cytokines. Bone loss will be monitored by micro computed tomography (µCT) scans. Finally, in different mouse models of periodontitis (P. gingivalis- and ligature-induced periodontal disease) we will interrogate the impact of E-cadherin/β-catenin signaling on LC/DC during infection and inflammation. Applying single-cell RNA sequencing the molecular pathways affected by E-cadherin/ β-catenin signals in oral mucosal LC/DC will be deciphered. Our expected findings may thus have important implications for designing improved LC/DC-based strategies for the treatment of periodontal disease.
If you are interested in this project, please select Clausen as your group preference in the IPP application platform.
Publications relevant to this project
Brand A, Hovav AH, Clausen BE (2023) Langerhans cells in the skin and oral mucosa - brothers in arms? Eur J Immunol. Feb 22:e2149499. doi: 10.1002/eji.202149499. PMID: 36811456 Link
Probst HC, Stoitzner P, Amon L, Backer RA, Brand A, Chen J, Clausen BE, Dieckmann S, Dudziak D, Heger L, Hodapp K, Hornsteiner F, Hovav AH, Jacobi L, Ji X, Kamenjarin N, Lahl K, Lahmar I, Lakus J, Lehmann CHK, Ortner D, Picard M, Roberti MP, Rossnagel L, Saba Y, Schalla C, Schlitzer A, Schraml BU, Schütze K, Seichter A, Seré K, Seretis A, Sopper S, Strandt H, Sykora MM, Theobald H, Tripp CH, Zitvogel L (2022) Guidelines for DC preparation and flow cytometry analysis of mouse nonlymphoid tissues. Eur J Immunol. Dec 13. doi: 10.1002/eji.202249819.PMID: 36512638 Link
Brand A, Diener N, Zahner SP, Tripp C, Ronald A. Backer RA, Karram K, Jiang A, Mellman I, Stoitzner P, Clausen BE (2020) E-cadherin is dispensable to maintain Langerhans cells in the epidermis; J Invest Dermatol. Jan;140(1):132-142.e3 doi: 10.1016/j.jid.2019.06.132. PMID: 31260672 Link
Capucha T, Koren N, Nassar M, Heyman O, Nir T, Levy M, Zilberman-Schapira G, Zelentova K, Eli-Berchoer L, Zenke M, Hieronymus T, Wilensky A, Bercovier H, Elinav E, Clausen BE, Hovav AH (2018) Sequential BMP7/TGF-β1 signaling and microbiota instruct mucosal Langerhans cell differentiation. J Exp Med.; 215(2):481-500. doi: 10.1084/jem.20171508.PMID: 29343501 Link