Role of endothelial Notch signaling in the regulation of tertiary lymphoid structures in renal homeostasis and response to kidney Injury

• Applicant: Professor Dr. Florian P. Limbourg
• Subject Area: Nephrology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575176966

Tertiary lymphoid structures (TLS) are inducible ectopic lymphoid tissues resembling lymph nodes that develop in parenchymal organs, such as the kidney, in response to injury or disease. A key vascular feature of TLS is their peri-arterial location and the presence of specialized high endothelial cells (HEC), found in high endothelial venules (HEV), which are critically involved in inflammatory and immune cell recruitment and migration. Notably, the transcriptomic profile of HEC shows upregulation of NF-κB signaling, but downregulation of the activity of the Notch signaling pathway, a cell fate regulator for arterial EC phenotype. We found previously that mice with endothelial-specific deletion of the Notch signal mediator Rbpj (Rbpj EC) spontaneously develop prototypical TLS in the kidney. EC from Notch-mutant mice showed a phenotype shift from arterial EC to HEC, accompanied by downregulation of Notch signaling components and upregulation of NF-κB signaling. We hypothesize that active Notch signaling maintains an arterial EC phenotype, preventing HEC phenotype shift. We also hypothesize that inflammatory conditions downregulate Notch signaling, which is a prerequisite for the development of HEC, likely in conjunction with NF-κB. We aim to investigate the mechanism that control endothelial arterial EC identity/maintenance and the consequences for HEC transdifferentiation and TLS formation in renal homeostasis and response to injury. Specifically, we will address the function of specific Notch receptors and ligands, the susceptible EC subpopulations and the potential modulation by inflammatory stimuli or disease context.

• DFG Programme: Research Grants