The kidney contains ontogenetically distinct dendritic cell and macrophage subtypes throughout development that differ in their inflammatory properties

Background Mononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental originof kidneyDCs 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 histocytometry 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 aDCorigin.Wedemonstrate 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 MHCIInegF4/80^hiCD11b^low 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 expressMHCII but lack TIM-4 andMERTK.MHCII⁺F4/80^hi cells exhibit prominent Clec9a-expression history in adulthood but not early life, indicating additional age-dependent developmental heterogeneity. In AKI, MHCIInegF4/80^hi cells reappear in adult kidneys as a result of MHCII downregulation by residentMHCII⁺F4/80^hi cells, possibly in response to prostaglandin E2 (PGE2). RNAsequencingfurther suggests MHCII⁺F4/80^hi cells help coordinate the recruitment of inflammatory cellsduring 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.