ADAM-mediated fine-tuning of antigen-presenting cell homeostasis and function in the intestine

• Applicant: Professor Dr. Björn Clausen
• Subject Area: Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 503972215

The mammalian intestinal tract represents a unique environment that is specialized in the efficient absorption of nutrients. Concurrently, a single epithelial cell layer separates deeper tissues from potentially harmful microbiota. Here, the immune system needs to establish a delicate balance between the host and the microbiome. Failure to maintain this homeostasis can result in chronic inflammatory bowel diseases (IBD). Antigen-presenting cells (APC), including macrophages (Mph) and conventional dendritic cells (cDC), are dedicated to maintaining tolerance towards food antigens and commensals while initiating immune responses to infections. While the importance of transcriptional control of these antagonistic APC functions is well established, the role of post-translational modifications (PTM) in fine-tuning their homeostasis and function in the intestine remains unclear. A-disintegrin-and-metalloproteinase (ADAM)-10 and ADAM17 are crucial for the shedding of cell surface substrates such as cytokines, chemokines, and their receptors, as well as phagocytic receptors, and adhesion molecules, thereby regulating the activity, localization, and interaction of many different cell types. Although both ADAMs and many of their potential targets are expressed by APC, the precise role of ADAM10 and ADAM17 in the homeostasis and function of intestinal APC is unknown. Thus, the overall aim of this project is to decipher ADAM-mediated PTM on Mph and cDC in maintaining immune homeostasis in the gut at steady-state and during inflammation. To this aim, we will analyze CD11c- and novel Mph/cDC subset-specific ADAM10 and ADAM17 single- and double-knockout mice. Our preparatory data indicate that ADAM10 primarily governs Mph and cDC homeostasis in the steady-state, while ADAM10 or ADAM17 regulate CD11c+ APC function in distinct IBD models. These intriguing findings warrant a detailed analysis of ADAM10 and ADAM17 on APC in the gut. Specifically, we will (1) unravel the impact of APC (subset)-specific ADAM10 and ADAM17 on immune homeostasis at steady-state, (2) perform a functional characterization of ADAM10- and ADAM17-deficient cDC, (3) determine the regulation of APC function by ADAM10 and ADAM17 during gut inflammation, and (4) characterize the molecular pathways affected by ADAM10 and ADAM17 in APC by single-cell RNA sequencing. This innovative research proposal will uncover the context-dependent importance of ADAM10- and ADAM17-mediated PTM to orchestrate intestinal APC biology, which may open new opportunities for cDC-based immunotherapeutic interventions in IBD.

• DFG Programme: Research Grants