New insights into the immune functions of podocytes: the role of complement.

IF 2.4 Q1 PEDIATRICS Molecular and cellular pediatrics Pub Date : 2023-04-15 DOI:10.1186/s40348-023-00157-3
Valentina Bruno, Anne Katrin Mühlig, Jun Oh, Christoph Licht
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引用次数: 1

Abstract

Podocytes are differentiated epithelial cells which play an essential role to ensure a normal function of the glomerular filtration barrier (GFB). In addition to their adhesive properties in maintaining the integrity of the filtration barrier, they have other functions, such as synthesis of components of the glomerular basement membrane (GBM), production of vascular endothelial growth factor (VEGF), release of inflammatory proteins, and expression of complement components. They also participate in the glomerular crosstalk through multiple signalling pathways, including endothelin-1, VEGF, transforming growth factor β (TGFβ), bone morphogenetic protein 7 (BMP-7), latent transforming growth factor β-binding protein 1 (LTBP1), and extracellular vesicles.Growing literature suggests that podocytes share many properties of innate and adaptive immunity, supporting a multifunctional role ensuring a healthy glomerulus. As consequence, the "immune podocyte" dysfunction is thought to be involved in the pathogenesis of several glomerular diseases, referred to as "podocytopathies." Multiple factors like mechanical, oxidative, and/or immunologic stressors can induce cell injury. The complement system, as part of both innate and adaptive immunity, can also define podocyte damage by several mechanisms, such as reactive oxygen species (ROS) generation, cytokine production, and endoplasmic reticulum stress, ultimately affecting the integrity of the cytoskeleton, with subsequent podocyte detachment from the GBM and onset of proteinuria.Interestingly, podocytes are found to be both source and target of complement-mediated injury. Podocytes express complement proteins which contribute to local complement activation. At the same time, they rely on several protective mechanisms to escape this damage. Podocytes express complement factor H (CFH), one of the main regulators of the complement cascade, as well as membrane-bound complement regulators like CD46 or membrane cofactor protein (MCP), CD55 or decay-accelerating factor (DAF), and CD59 or defensin. Further mechanisms, like autophagy or actin-based endocytosis, are also involved to ensure podocyte homeostasis and protection against injury.This review will provide an overview of the immune functions of podocytes and their response to immune-mediated injury, focusing on the pathogenic link between complement and podocyte damage.

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足细胞免疫功能的新认识:补体的作用。
足细胞是一种分化的上皮细胞,对确保肾小球滤过屏障(GFB)的正常功能起着至关重要的作用。除了具有维持滤过屏障完整性的粘附特性外,它们还有其他功能,如合成肾小球基底膜(GBM)成分、产生血管内皮生长因子(VEGF)、释放炎症蛋白和表达补体成分。它们还通过内皮素-1、VEGF、转化生长因子β (TGFβ)、骨形态发生蛋白7 (BMP-7)、潜伏转化生长因子β结合蛋白1 (LTBP1)和细胞外囊泡等多种信号通路参与肾小球串音。越来越多的文献表明足细胞具有先天免疫和适应性免疫的许多特性,支持确保健康肾小球的多功能作用。因此,“免疫足细胞”功能障碍被认为与几种肾小球疾病(称为“足细胞病”)的发病机制有关。机械性、氧化性和/或免疫应激等多种因素可诱导细胞损伤。作为先天免疫和适应性免疫的一部分,补体系统也可以通过多种机制定义足细胞损伤,如活性氧(ROS)的产生、细胞因子的产生和内质网应激,最终影响细胞骨架的完整性,导致足细胞脱离GBM和蛋白尿的发生。有趣的是,足细胞被发现是补体介导的损伤的来源和目标。足细胞表达补体蛋白,促进局部补体活化。同时,它们依靠几种保护机制来逃避这种伤害。足细胞表达补体因子H (CFH),补体级联的主要调节因子之一,以及膜结合的补体调节因子如CD46或膜辅助因子蛋白(MCP), CD55或衰变加速因子(DAF), CD59或防御素。进一步的机制,如自噬或基于动作蛋白的内吞作用,也参与确保足细胞稳态和保护免受损伤。本文将对足细胞的免疫功能及其对免疫介导损伤的反应进行综述,重点讨论补体与足细胞损伤之间的致病关系。
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