TNFR2 Regulation of Leukocyte Recruitment in Glomerulonephritis

肾小球肾炎中白细胞募集的 TNFR2 调节

基本信息

批准号：
8821615
负责人：
Tanya N Mayadas
金额：
$ 42.96万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8821615
关键词：
Acute Address Affinity Animal Model Attenuated Autocrine Communication Behavior Binding Biological Blocking Antibodies Blood Blood capillaries Bone Marrow CXCR3 gene Cell Culture Techniques Cells Chemotactic Factors Chimera organism Chronic Data Development Disease Disease Progression End stage renal failure Endothelial Cells Endothelium Evolution Functional disorder Generations Glomerular Capillary Glomerular basement membrane antibody Glomerulonephritis Health Human IFNAR1 gene Image Imaging Techniques Immunity Immunotherapeutic agent In Situ Infiltration Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Interferon Regulatory Factor 1 Interferon-alpha Kidney Kidney Diseases Knockout Mice Label Lead Leukocyte Trafficking Leukocytes Link Membrane Modeling Molecular Mononuclear Mus Nephritis Organ Organ Culture Techniques Pathogenesis Pathway interactions Patients Physiological Production Publishing Receptor Signaling Recombinants Recruitment Activity Regulation Relative (related person)Reporter Role Route Sampling Signal Pathway Signal Transduction TNF gene TNFRSF1A gene TNFRSF1B gene Testing Time Tissues Transforming Growth Factor beta Transgenic Mice Vascular Endothelium antibody conjugate autocrine base capillary chemokine cytokine glomerular basement membrane glomerular endothelium in vivo insight intravital microscopy kidney cell kidney imaging macrophage monocyte neutrophil new therapeutic target novel prevent receptor response spatiotemporal trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Leukocyte accumulation is a hallmark of inflammatory renal diseases. TNF, a potent cytokine that regulates leukocyte trafficking is essential for the development of glomerulonephritis in animal models. Many of the pro- inflammatory responses of TNF in vivo can be attributed to its effects on the vascular endothelium and leukocyte influx. TNF relays its biological activities by two distinct receptors, TNFR1 and TNFR2 with most of TNF's effects on the endothelium being attributed to TNFR1. The contribution of TNFR2 is likely underestimated as it has a higher affinity for the membrane bound versus the soluble form of the cytokine and it is not constitutively expressed in all endothelial cell cultures. Our recently published data demonstrate that engagement of TNFR2 in cultured endothelial cells triggers Interferon regulatory factor-1 (IRF-1) induced IFNß synthesis, and subsequent autocrine signaling via the IFNα/ß receptor, to generate mononuclear cell chemoattractants. In vivo, acute renal inflammation induced by intravenously administered recombinant TNF results in neutrophil and monocyte recruitment in the kidney that requires TNFR1, while the TNFR2-IRF-1- IFNß autocrine loop is essential only for monocyte/macrophage accumulation. In a chronic model of anti- glomerular basement membrane nephritis, renal TNFR2 and IRF-1 but not TNFR1 are essential for sustained macrophage accumulation. Thus, our data identify a previously unrecognized TNFR2-IRF-1-IFNß-IFNα/ß receptor-signaling pathway in endothelial cells that promotes monocyte recruitment. These findings may have relevance in humans as TNFR2, absent in normal human kidney, is robustly induced on the glomerular endothelium of patients with anti-GBM nephritis. Our results raise two important questions: How does TNFR2 induce IRF-1, and what steps of leukocyte recruitment in the kidney are regulated by TNFR2 and its associated IFNß autocrine loop? These questions will be addressed in three specific aims: I) Delineate TNFR2 proximal intracellular signals that link TNFR2 to IRF-1 and IFNß production; II) Conduct intravital microscopy in the intact kidney to elucidate pathways of renal leukocyte recruitment triggered by TNF; and III) Elucidate the molecular requirements for renal TNFR2 and components of the IFNß autocrine loop in the dynamics of monocyte recruitment. For Aims II and III, we have developed a multiphoton intravital microscopy approach for time-lapse imaging of leukocyte behavior in the glomerular and peritubular capillaries of mice. Determining how TNF-induced amplification of IFNß expression and IFNß-signaling locally in the endothelium leads to monocyte accumulation in the kidney could result in important new insights into the pathogenesis of glomerulonephritis and lead to new therapeutic targets.

描述（由申请人提供）：白细胞积聚是炎症性肾病的标志，TNF是一种调节白细胞运输的有效细胞因子，对于动物模型中肾小球肾炎的发展至关重要。由于其对血管内皮和白细胞流入的影响，TNF 通过两种不同的受体 TNFR1 和 TNFR2 传递其生物活性。 TNF 对内皮细胞的影响归因于 TNFR1，TNFR2 的贡献可能被低估，因为与可溶形式的细胞因子相比，它对膜结合的亲和力更高，而且我们最近发表的数据并未组成型表达。证明 TNFR2 在培养的内皮细胞中的参与会触发干扰素调节因子-1 (IRF-1) 诱导的 IFNβ 合成，以及随后通过IFNα/β 受体，产生单核细胞趋化剂。在体内，静脉注射重组 TNF 诱导的急性肾脏炎症会导致肾脏中需要 TNFR1 的中性粒细胞和单核细胞募集，而 TNFR2-IRF-1- IFNβ 自分泌环则被抑制。仅在抗肾小球基底膜肾炎的慢性模型中，肾 TNFR2 和巨噬细胞积聚是必需的。 IRF-1 而不是 TNFR1 对于巨噬细胞的持续积累至关重要，因此，我们的数据发现了内皮细胞中以前未被识别的 TNFR2-IRF-1-IFNß-IFNα/ß 受体信号通路，这些发现可能具有促进单核细胞募集的作用。 TNFR2 在人类中的相关性在正常人肾脏中不存在，但在抗 GBM 肾炎患者的肾小球内皮上被强烈诱导。提出了两个重要问题：TNFR2 如何诱导 IRF-1，以及 TNFR2 及其相关的 IFNβ 自分泌环调节肾脏中白细胞募集的哪些步骤？这些问题将通过三个具体目标得到解决：I) 描绘 TNFR2 近端细胞内信号将 TNFR2 与 IRF-1 和 IFNβ 产生联系起来 II) 在完整肾脏中进行活体显微镜检查，以阐明触发肾白细胞募集的途径；通过 TNF；和 III) 阐明单核细胞募集动态中肾脏 TNFR2 和 IFNβ 自分泌环的分子需求。对于目标 II 和 III，我们开发了一种多光子活体显微镜方法，用于白细胞行为的延时成像。确定小鼠肾小球和肾小管周围毛细血管如何 TNF 诱导 IFNβ 表达和 IFNβ 信号放大。在内皮细胞局部导致单核细胞在肾脏中积聚，可能会给肾小球肾炎的发病机制带来重要的新见解，并产生新的治疗靶点。