Renal Macrophage Biology

肾巨噬细胞生物学

• 批准号: 10452251
• 负责人: Xuebin Qin
• 金额: $ 51.07万
• 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/10452251
• 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; 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; alpha Toxin; design; improved; macrophage; metabolic profile; monocyte; normal aging; 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.

项目摘要/摘要 肾巨噬细胞(RMS)是驻留在肾组织中的髓系细胞，履行特定的肾脏功能，包括 动态平衡、免疫监视和修复。RMS约占CD45+白细胞总数的50% 老鼠的肾脏和人类肾脏中也发现了大量的病毒。它们由胚胎来源的 (EMRM)和骨髓(BM)RMS(BMRM)。最近，艾德等人。发现卵黄囊来源的肾脏 巨噬细胞(YSRM)[5]在出生时只占RMS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RM数量的主要贡献者。巨噬细胞的生态位在 脑、肝和肺等组织可能决定组织巨噬细胞(TM)的特定功能。 对于这些TM，只有少量的利基信号被描述，并且特定的分子 Rm再生的机制还没有被研究。理解RM的机制 利基市场将是肾脏疾病治疗方法发展的关键，这些疾病可以阻断或诱导特定的 信号通路。RM生态位如何影响RM的寿命、命运、动态和免疫代谢反应 目前仍不清楚。为了解决这些问题，我们应用了最近产生的Cre诱导的人CD59 利用转基因系(IhCD59)追踪骨髓或胚胎的RMS谱系及RMS的内在特性 起源。我们发现，RMS主要来源于出生前的胎儿肝脏单核细胞，但在出生后 成年期外周血单核细胞的贡献。在稳定状态下，CX3CR1缺乏，但不是 CCR2显著减少了从出生到成年的RMS数量，但不会减少小胶质细胞的数量。我们的 初步结果表明，CX3CR1/CX3CL1轴对于特定的再生和 RMS的维护。尽管CX3CR1/CX3CL1在多种组织疾病进展中的作用 (包括肾组织)已经被认识到很多年了，它在RMS的这个利基信号中起着关键作用 BM、胚胎和卵黄囊的起源尚未被研究过。Fractalkine/CX3CL1以膜的形式存在- 锚定的分子以及可溶的形式，每一种都调节不同的生物活性。然而，这些角色 对于这两种类型的CX3CL1在Rm中的再生和维持尚不清楚。因此，我们建议 为了检验我们的工作假设，即CX3CL1信号通路对CX3CR1+RM的长寿至关重要， 在正常(目标1)和病理条件(目标2)下的命运、动态和免疫代谢反应。在……里面 目的3，我们将研究CX3CR1/CX3CL1轴的细胞和分子机制 具体地说，是关于RM的再生和维护。这些目标的成功实现将推动我们的 了解组织巨噬细胞生物学，特别是RMS，这将有助于改进设计和 肾脏疾病治疗方法的发展，阻断或诱导特定的信号通路。