Neonatal Fc Receptor (FcRn) Trafficking of Immune Complexes to the Lysosome as a Driver of Glomerulonephritis

新生儿 Fc 受体 (FcRn) 将免疫复合物运输到溶酶体作为肾小球肾炎的驱动因素

基本信息

批准号：
10535435
负责人：
JUDITH T., BLAINE
金额：
$ 40.55万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535435
关键词：
Aftercare Albumins Animal Model Antigen-Antibody Complex Apoptosis Apoptotic Biochemical Biological Response Modifiers CD8B1 gene Cathepsins Cathepsins B Cell Death Cell Membrane Permeability Cells Cessation of life Cytosol Degradation Pathway Dendritic Cells Deposition Disease Disease Progression Disease model End stage renal failure Endothelial Cells Enzymes Extravasation FOXP3 gene Fc Receptor Functional disorder Glomerulonephritis Goals Health Histologic Histology Human Imaging Techniques Immune Immune Targeting Immunoglobulin G Immunological Models Induction of Apoptosis Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Location Lupus Nephritis Lysosomes Macrophage Mediating Mediator Membranous Glomerulonephritis Methods Mitochondria Modeling Morbidity - disease rate Mus Nephritis Outer Mitochondrial Membrane Pathway interactions Patients Permeability Play Proteinuria Proteolytic Processing Research Role Serum Severity of illness Signal Transduction Sorting Structure T-Lymphocyte Testing Up-Regulation Work cell type cytochrome c glomerular filtration glomerulosclerosis human model improved in vivo in vivo Model insight interest mitochondrial membrane monomer mortality mouse model neonatal Fc receptor nephrotoxicity neutrophil novel podocyte preservation prevent response targeted treatment trafficking transcriptome sequencing

项目摘要

Abstract/Project Summary Immune mediated kidney diseases cause substantial morbidity and often lead to progressive renal failure. Immune complexes (ICs) have been found in podocytes in a variety of immune mediated kidney diseases but it is not known how podocytes handle immune complexes and whether trafficking of immune complexes in podocytes exacerbates glomerulonephritis. The neonatal Fc receptor (FcRn) correctly sorts and traffics ICs in a variety of cells including podocytes. FcRn is also required to traffic immune complexes to the lysosome in dendritic cells for proteolytic processing and presentation on MHC II. In preliminary studies, we have found that podocyte specific knockout of FcRn protects in two models of immune mediated nephritis but that this protection is not conferred by an immune mediated mechanism. While there is no difference in any of the immune parameters examined, we have found that there is significantly less apoptotic cell death and upregulation of apoptotic pathways in FcRn knockout (KO) podocytes treated with immune complexes and significantly decreased apoptosis in the glomeruli of podocyte specific FcRn KO mice after induction of nephrotoxic serum nephritis (NTS). In addition, we have found significantly less lysosomal activation and less upregulation of lysosomal enzymes in FcRn KO podocytes treated with immune complexes. Since FcRn is required to traffic immune complexes to the lysosome, we hypothesize that in immune mediated nephritis, FcRn directed trafficking of ICs to the lysosome results in lysosomal dysfunction, upregulation of the intrinsic apoptotic pathway and podocyte death. To test this hypothesis we will directly examine lysosomal structure and function in WT and FcRn KO podocytes after an immune challenge using both advanced imaging techniques and biochemical methods. We will also examine whether FcRn mediated trafficking of immune complexes to the lysosome results in increased lysosomal permeability and leakage of lysosomal cathepsins into the cytosol causing degradation of mitochondrial membrane integrity, leakage of cytochrome c and upregulation of intrinsic apoptotic pathways. We will test whether podocyte specific knockout of FcRn results in decreased lysosomal activation and improved lysosomal function in podocytes in vivo after induction of immune mediated kidney disease (NTS) and whether this in turn results in less apoptotic cell death, an increased number of viable podocytes and less severe disease as assessed by functional and histologic parameters. Since upregulation of lysosomal cathepsins correlates with more severe lupus nephritis in patients, we will also examine whether podocyte specific knockout of FcRn ameliorates lupus nephritis in a spontaneous mouse model of this disease. Taken together, the proposed work will provide novel insights into FcRn mediated trafficking of immune complexes in podocytes and may allow for the creation of targeted therapies to slow or prevent progression of immune mediated glomerulonephritis.

摘要/项目摘要免疫介导的肾脏疾病会导致大量发病率，并经常导致肾衰竭。在多种免疫介导的肾脏疾病的足细胞中发现了免疫复合物（IC），但尚不知道足细胞如何处理免疫复合物以及免疫复合物的运输是否在足细胞加剧肾小球肾炎。新生儿FC受体（FCRN）正确地分类了AC 包括足细胞在内的各种细胞。还需要FCRN将免疫复合物传输到溶酶体中在MHC II上进行蛋白水解加工和表现的树突状细胞。在初步研究中，我们发现 FCRN的足细胞特异性敲除在两种免疫介导的肾炎模型中保护不受免疫介导的机制赋予。虽然任何免疫都没有差异检查了参数，我们发现凋亡细胞死亡和上调明显较少用免疫复合物处理的FCRN敲除（KO）足细胞中的凋亡途径诱导肾毒性血清后足细胞特异性FCRN KO小鼠的肾小球凋亡降低肾炎（NTS）。此外，我们发现溶酶体激活明显较少，上调的上调用免疫复合物处理的FCRN KO足细胞中的溶酶体酶。由于需要fcrn流量免疫复合物对溶酶体，我们假设在免疫介导的肾炎中，FCRN指导运输溶酶体的ICS导致溶酶体功能障碍，内在凋亡途径的上调和足细胞死亡。为了检验这一假设，我们将直接检查WT中的溶酶体结构和功能通过先进的成像技术和生化，免疫挑战后的FCRN KO足细胞方法。我们还将检查FCRN是否介导了免疫复合物对溶酶体结果的运输在增加的溶酶体渗透性和溶酶体组织蛋白酶渗漏到细胞质中，导致降解线粒体膜完整性，细胞色素C的泄漏以及内在凋亡途径的上调。我们将测试FCRN的Podocyte特异性敲除是否导致溶酶体激活降低并改善免疫介导的肾脏疾病（NTS）诱导后体内足细胞中的溶酶体功能这反过如功能和组织学参数所评估。由于溶酶体组织蛋白的上调与患者中更严重的狼疮肾炎，我们还将检查Podocyte特异性敲除FCRN的特异性敲除在这种疾病的自发小鼠模型中改善狼疮肾炎。两者一起，拟议的工作将提供有关FCRN介导的型免疫复合物的介导的洞察力的新见解，并可能允许产生靶向疗法以减慢或防止免疫介导的肾小球肾炎的进展。