Plasticity and Phenotype of Kidney-Resident Macrophages (krMΦs) and their Modulation for Improved Allograft Outcome post Transplantation

• Applicants: Professorin Katja Kotsch, Ph.D.; Dr. Efstathios Stamatiades
• Subject Area: General and Visceral Surgery ; Nephrology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552076746

Myeloid cell infiltration is a hallmark of renal inflammation in experimental models and human disease. For instance, in inflamed tissues, monocytes extravasate, acquire proinflammatory features, and differentiate into macrophages. In the kidney, such monocyte-derived macrophages (mdMΦs) are phenotypically almost indistinguishable from kidney-resident macrophages (krMΦs), which develop during embryogenesis, are self-maintained and are distributed throughout the renal interstitium. This hampers the precise discrimination between mdMΦs and krMΦs, and, in turn, the assessment of their relative contribution to tissue repair or injury. For instance, in renal transplantation, long term allograft survival is still an unmet clinical need and the widening gap between patients on the waiting list and available donor organs results results in the expansion of the donor pool by the acceptance of expanded criteria donor (ECD) organs, showing a higher risk of unfavorable outcomes. Although monocytes and krMΦs have been documented to play a role during the rejection response, their precise role for graft survival has not been sufficiently explored, particularly in terms of donor-related risk factors (ageing). There is accumulating evidence that distinct macrophage subsets play important, yet opposing, roles in determining the fate (rejection versus acceptance) of kidney grafts. Given that krMΦs of donor origin might temporarily persist in the transplant and shape the alloimmune response, studying the role of krMΦs in graft survival – albeit complex – offers new opportunities for modulation the microenvironment for allograft survival. Using state-of-the-art techniques including genetic fate mapping, RNA sequencing, confocal/intravital/light-sheet fluorescence microscopy, we will decipher renal macrophage biology in steady state and renal transplantation. We will further explore how risk factors including age re-shape the phenotype of krMΦs and its consequences for the outcome of kidney grafts. Experimental animal studies will be complemented by a comprehensive analysis of monocytes/macrophages from patient tissues. Collectively, our work will identify novel therapeutic targets within the complex network of donor and recipient-derived krMΦs for protection of the (marginal) allograft.

• DFG Programme: Research Grants