Fucose as a new therapeutic target in renal transplantation.
Fucose as a new therapeutic target in renal transplantation.
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DOI：
10.1007/s00467-020-04588-2
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Sacks SH
中科院分区：
文献类型：
--
作者：
Howard MC;Nauser CL;Vizitiu DA;Sacks SH
缺血/再灌注损伤（IRI）是肾移植过程中不可避免的损害性后果，最终导致移植物功能延迟和移植物丢失风险增加。肾脏中这种不良反应的关键驱动因素是补体系统的激活，补体系统是先天免疫系统的重要组成部分。这种激活导致补体C3在肾小管上的沉积以及免疫细胞的浸润，并最终损害肾小管，导致肾功能降低。凝集素-11（Collectin-11，CL-11）是补体凝集素途径的模式识别分子。CL-11与IRI引起的应激暴露在肾小管上的配体结合，通过附着的蛋白酶，CL-11激活补体，这有助于上述结果。我们实验室最近的工作表明，这种损伤相关配体含有一个岩藻糖残基，有助于CL-11结合并促进补体激活。在这篇综述中，我们将讨论肾移植的临床背景，IRI的补体系统的相关性，并概述CL-11结合岩藻糖基化配体在IRI的作用以及其下游效应的证据。最后，我们将详细介绍简单但优雅的理论，即增加肾脏中游离岩藻糖的水平作为诱饵分子，大大降低了CL-11介导的IRI的临床后果。
Ischaemia/reperfusion injury (IRI) is an inevitable and damaging consequence of the process of kidney transplantation, ultimately leading to delayed graft function and increased risk of graft loss. A key driver of this adverse reaction in kidneys is activation of the complement system, an important part of the innate immune system. This activation causes deposition of complement C3 on renal tubules as well as infiltration of immune cells and ultimately damage to the tubules resulting in reduced kidney function. Collectin-11 (CL-11) is a pattern recognition molecule of the lectin pathway of complement. CL-11 binds to a ligand that is exposed on the renal tubules by the stress caused by IRI, and through attached proteases, CL-11 activates complement and this contributes to the consequences outlined above. Recent work in our lab has shown that this damage-associated ligand contains a fucose residue that aids CL-11 binding and promotes complement activation. In this review, we will discuss the clinical context of renal transplantation, the relevance of the complement system in IRI, and outline the evidence for the role of CL-11 binding to a fucosylated ligand in IRI as well as its downstream effects. Finally, we will detail the simple but elegant theory that increasing the level of free fucose in the kidney acts as a decoy molecule, greatly reducing the clinical consequences of IRI mediated by CL-11.
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