Natallia Salei1,2, Stephan Rambichler1,2, Johanna Salvermoser1,2, Nikos E Papaioannou1,2, Ronja Schuchert3,4, Dalia Pakalniškytė1,2, Na Li5,6, Julian A Marschner6, Julia Lichtnekert6, Christopher Stremmel3,4, Filippo M Cernilogar7, Melanie Salvermoser1,2, Barbara Walzog1,2, Tobias Straub8, Gunnar Schotta7,9, Hans-Joachim Anders6, Christian Schulz3,4, Barbara U Schraml10,2. 1. Walter Brendel Centre of Experimental Medicine, University Hospital Munich. 2. Institute for Cardiovascular Physiology and Pathophysiology. 3. Medical Clinic and Polyclinic I and. 4. DZHK (Deutsches Zentrum für Herz-Kreislaufforschung [German Center for Cardiovascular Research]), Partner Site Munich Heart Alliance, Munich, Germany; and. 5. Division of Nephrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shen Zhen, China. 6. Division of Nephrology, Medical Clinic and Polyclinic IV, University Hospital Munich, Ludwig Maximilian University of Munich, Munich, Germany. 7. Division of Molecular Biology. 8. Core Facility Bioinformatics, and. 9. Center for Integrated Protein Science Munich, Biomedical Center, Faculty of Medicine, Ludwig Maximilian University of Munich, Martinsried, Germany. 10. Walter Brendel Centre of Experimental Medicine, University Hospital Munich, barbara.schraml@med.uni-muenchen.de.
Abstract
BACKGROUND: Mononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental origin of kidney DCs has been highly debated because of the large phenotypic overlap between macrophages and DCs in this tissue. METHODS: We used fate mapping, RNA sequencing, flow cytometry, confocal microscopy, and histo-cytometry to assess the origin and phenotypic and functional properties of renal DCs in healthy kidney and of DCs after cisplatin and ischemia reperfusion-induced kidney injury. RESULTS: Adult kidney contains at least four subsets of MPs with prominent Clec9a-expression history indicating a DC origin. We demonstrate that these populations are phenotypically, functionally, and transcriptionally distinct from each other. We also show these kidney MPs exhibit unique age-dependent developmental heterogeneity. Kidneys from newborn mice contain a prominent population of embryonic-derived MHCIInegF4/80hiCD11blow macrophages that express T cell Ig and mucin domain containing 4 (TIM-4) and MER receptor tyrosine kinase (MERTK). These macrophages are replaced within a few weeks after birth by phenotypically similar cells that express MHCII but lack TIM-4 and MERTK. MHCII+F4/80hi cells exhibit prominent Clec9a-expression history in adulthood but not early life, indicating additional age-dependent developmental heterogeneity. In AKI, MHCIInegF4/80hi cells reappear in adult kidneys as a result of MHCII downregulation by resident MHCII+F4/80hi cells, possibly in response to prostaglandin E2 (PGE2). RNA sequencing further suggests MHCII+F4/80hi cells help coordinate the recruitment of inflammatory cells during renal injury. CONCLUSIONS: Distinct developmental programs contribute to renal DC and macrophage populations throughout life, which could have important implications for therapies targeting these cells.
BACKGROUND: Mononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental origin of kidney DCs has been highly debated because of the large phenotypic overlap between macrophages and DCs in this tissue. METHODS: We used fate mapping, RNA sequencing, flow cytometry, confocal microscopy, and histo-cytometry to assess the origin and phenotypic and functional properties of renal DCs in healthy kidney and of DCs after cisplatin and ischemia reperfusion-induced kidney injury. RESULTS: Adult kidney contains at least four subsets of MPs with prominent Clec9a-expression history indicating a DC origin. We demonstrate that these populations are phenotypically, functionally, and transcriptionally distinct from each other. We also show these kidney MPs exhibit unique age-dependent developmental heterogeneity. Kidneys from newborn mice contain a prominent population of embryonic-derived MHCIInegF4/80hiCD11blow macrophages that express T cell Ig and mucin domain containing 4 (TIM-4) and MER receptor tyrosine kinase (MERTK). These macrophages are replaced within a few weeks after birth by phenotypically similar cells that express MHCII but lack TIM-4 and MERTK. MHCII+F4/80hi cells exhibit prominent Clec9a-expression history in adulthood but not early life, indicating additional age-dependent developmental heterogeneity. In AKI, MHCIInegF4/80hi cells reappear in adult kidneys as a result of MHCII downregulation by resident MHCII+F4/80hi cells, possibly in response to prostaglandin E2 (PGE2). RNA sequencing further suggests MHCII+F4/80hi cells help coordinate the recruitment of inflammatory cells during renal injury. CONCLUSIONS: Distinct developmental programs contribute to renal DC and macrophage populations throughout life, which could have important implications for therapies targeting these cells.
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