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.

中文翻译：

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肾脏在整个发育过程中均包含个体发育不同的树突状细胞和巨噬细胞亚型，这些亚型具有不同的炎症特性。

背景技术包括巨噬细胞，单核细胞和树突细胞（DC）的单核吞噬细胞（MP）是在免疫中起重要作用的吞噬细胞。由于该组织中巨噬细胞和DC之间存在大量的表型重叠，因此肾脏DC的发育起源受到了广泛的争议。方法我们使用命运图谱，RNA测序，流式细胞术，共聚焦显微镜和组织细胞术评估健康的肾脏中DC的起源，表型和功能特性，以及顺铂和局部缺血再灌注引起的肾损伤后DC的表现。结果成年肾脏包含至少四个具有显着Clec9a表达史的MP子集，表明其DC起源。我们证明这些人口是表型，功能和转录彼此不同。我们还显示这些肾脏议员表现出独特的年龄依赖性发育异质性。新生小鼠的肾脏中有大量的胚胎来源的MHCIInegF4 / 80hiCD11blow巨噬细胞，它们表达T细胞Ig和含有4（TIM-4）和MER受体酪氨酸激酶（MERTK）的粘蛋白结构域。这些巨噬细胞在出生后的几周内被表型相似的表达MHCII但缺乏TIM-4和MERTK的细胞所替代。MHCII + F4 / 80hi细胞在成年期表现出突出的Clec9a表达历史，但没有早年生活，这表明其年龄依赖性的发育异质性更高。在AKI中，由于常驻MHCII + F4 / 80hi细胞下调了MHCII，MHCIInegF4 / 80hi细胞重新出现在成年肾脏中，这可能是对前列腺素E2（PGE2）的反应。RNA测序进一步表明，MHCII + F4 / 80hi细胞有助于协调肾损伤期间炎症细胞的募集。结论不同的发育计划对终生的肾DC和巨噬细胞群有贡献，这可能对靶向这些细胞的疗法具有重要意义。