The Kidney Contains Ontogenetically Distinct Dendritic Cell and Macrophage Subtypes throughout Development That Differ in Their Inflammatory Properties
Authors: Salei Natallia , Rambichler Stephan , Salvermoser Johanna , Papaioannou Nikos E. , Schuchert Ronja , Pakalniškytė Dalia , Li Na , Marschner Julian A. , Lichtnekert Julia , Stremmel Christopher , Cernilogar Filippo M. , Salvermoser Melanie , Walzog Barbara , Straub Tobias , Schotta Gunnar , Anders Hans-Joachim , Schulz Christian , Schraml Barbara U. 
Published: January 2020

Significance Statement
The origin of kidney dendritic cells (DCs) has been highly debated because they share many phenotypic traits with macrophages in this tissue. Using fate mapping, the authors demonstrate that kidneys from adult mice contain four subsets of DCs unique age-dependent differences in DCs and macrophages. Renal embryonic-derived macrophages are replaced shortly after birth by phenotypically similar cells arising from hematopoiesis. In adults, these are generated from DC progenitors. In two models of renal injury, cells resembling embryonic-derived macrophages reappear in inflamed kidneys as a result from MHCII downregulation from renal dendritic cells. Understanding age-dependent developmental aspects in these cells of immune-modulatory and antigen-presenting function may help scientists develop therapies targeting them.

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.