Renal Macrophage Biology

肾巨噬细胞生物学

• 批准号: 10610904
• 负责人: Xuebin Qin
• 金额: $ 51.09万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610904
• 关键词: Ablation; Acute; Address; Adult; Age; Aging; Antibodies; Binding; Biological; Biology; Birth; Bone Marrow; Brain; CX3CL1 gene; Cell surface; Cells; Coculture Techniques; Complement; Cre driver; Development; Disease; Embryo; Epithelial Cells; Fetal Liver; Flow Cytometry; Fluorescence; Fractalkine; Genetic Recombination; Glomerulonephritis; Homeostasis; Human; Immune; Immunologic Surveillance; In Vitro; Injections; Kidney; Kidney Diseases; Knock-out; Label; Leukocytes; Liver; Longevity; Lung; Macrophage; Maintenance; Mediating; Membrane; Metabolic; Modeling; Molecular; Mus; Myeloid Cells; Natural regeneration; PTPRC gene; Pathologic; Peripheral; Population; Process; Property; Protein Isoforms; Renal Tissue; Renal function; Reperfusion Injury; Reporter; Reporting; Role; Serum; Signal Pathway; Signal Transduction; Stains; Streptococcus intermedius; System; Testing; Tissues; Toxin; Transgenic Organisms; Tubular formation; Yolk Sac; aged; design; improved; inducible Cre; metabolic profile; monocyte; novel; renal ischemia; repaired; response; single-cell RNA sequencing; therapeutic development

PROJECT SUMMARY/ABSTRACT Renal macrophages (RMs) are myeloid cells residing in renal tissue that fulfill specific renal functions including homeostasis, immune surveillance, and repair. RMs account for about 50% of total CD45+ leukocytes in mouse kidneys and are also found in large numbers in the human kidney. They consist of embryo-derived (EMRMs) and bone marrow (BM)-derived RMs (BMRMs). Recently, Ide, et al. found that yolk-sac-derived renal macrophages (YSRMs)[5] contribute a very small portion of RMs at birth, but progressively expand in number with age and become a major contributor to the RM population in older mice. The macrophages’ niche in tissues such as brain, liver, and lung may determine the specific functions of the tissue macrophages (TMs). Only a small number of the niche signals have been described for these TMs, and the specific molecular mechanism underlying RM regeneration has not been studied. Understanding the mechanisms of the RM niches will be critical to the development of therapeutics for kidney diseases that block or induce specific signaling pathways. How RM niches impact RM longevity, fate, dynamics, and immune metabolic responses remains unclear. To address these questions, we have applied a recently generated Cre induced-human CD59 transgenic line (ihCD59) to trace RM lineage and determine the intrinsic properties of RMs of BM or embryonic origins. We find that RMs are mainly derived from fetal liver monocytes before birth, but self-maintain through adulthood with contributions from peripheral monocytes. At a steady state, deficiency of CX3CR1, but not of CCR2, significantly reduces the number of RMs, but not microglia, from birth through adulthood. Our preliminary results suggest the CX3CR1/CX3CL1 axis is indispensable for specific regeneration and maintenance of RMs. Although the role of CX3CR1/CX3CL1 in the progression of various diseases in tissues (including kidney tissue) has been recognized for many years, its critical role in this niche signaling for RMs of BM, embryonic, and yolk-sac origins has not been studied. Fractalkine/CX3CL1 exists as a membrane- anchored molecule as well as in soluble form, each mediating different biological activities. However, the roles for these two types of CX3CL1 in RM regeneration and maintenance remain unknown. Therefore, we propose to examine our working hypothesis that the CX3CL1 signaling pathway is critical for CX3CR1+RM longevity, fate, dynamics, and immune metabolic responses under normal (Aim 1) and pathological conditions (Aim 2). In Aim 3, we will examine the cellular and molecular mechanisms by which the CX3CR1/CX3CL1 axis contributes specifically to RM regeneration and maintenance. Successful completion of these Aims will advance our understanding of tissue macrophage biology, and specifically of RMs which will allow for improved design and development of therapeutics for kidney disease that block or induce specific signaling pathways.

项目总结/摘要 肾巨噬细胞（RM）是存在于肾组织中的髓样细胞，其实现特定的肾功能，包括 稳态、免疫监视和修复。RM占CD45+白细胞总数的约50%。 小鼠肾脏中也有大量存在，人类肾脏中也有大量存在。它们由胚胎来源的 （EMRM）和骨髓（BM）来源的RM（BMRM）。最近，Ide等人发现，卵黄囊来源的肾 巨噬细胞（YSRMs）[5]在出生时只占RM的很小一部分，但数量逐渐增加 随着年龄的增长，并成为老年小鼠中RM群体的主要贡献者。巨噬细胞的小生境 组织如脑、肝和肺可决定组织巨噬细胞（TM）的特定功能。 只有少数的生态位信号已被描述为这些TM，和特定的分子 RM再生的机理尚未研究。了解RM的机制 小生境对于开发肾脏疾病的治疗方法至关重要， 信号通路RM生态位如何影响RM寿命、命运、动力学和免疫代谢反应 仍不清楚为了解决这些问题，我们应用了最近产生的Cre诱导的人CD59 转基因系（ihCD59）以追踪RM谱系并确定BM或胚胎RM的内在特性 起源.我们发现RM主要来源于出生前的胎肝单核细胞，但通过 成年期外周血单核细胞的贡献。在稳定状态下，CX3CR1缺乏，而不是CX3CR2缺乏。 从出生到成年，CCR2显着减少RM的数量，但不是小胶质细胞。我们 初步结果表明CX3CR1/CX3CL1轴对于特异性再生是必不可少的， RM的维护。尽管CX3CR1/CX3CL1在组织中各种疾病的进展中的作用 （包括肾组织）已经被认识了很多年，它在RM的这种生态位信号传导中的关键作用， BM、胚胎和卵黄囊起源尚未研究。Fractalkine/CX3CL1作为膜存在- 锚定分子以及可溶形式，每种介导不同的生物活性。然而，角色 对于这两种类型的CX 3CL 1在RM再生和维持中的作用仍然未知。所以我们提出 为了检验我们的工作假设，即CX3CL1信号通路对CX3CR1 + RM寿命至关重要， 命运，动力学和免疫代谢反应在正常（目标1）和病理条件下（目标2）。在 目的3，我们将研究CX3CR1/CX3CL1轴参与的细胞和分子机制 特别是RM再生和维护。成功实现这些目标将推动我们的 理解组织巨噬细胞生物学，特别是RM，这将允许改进设计和 开发阻断或诱导特定信号传导途径的肾病治疗剂。