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巨噬细胞极化及与肾小管上皮细胞互动在缺血再灌注所致急性肾损伤中的作用

王薇¹, 赛文莉², 杨斌^1,3,*

¹南通-莱斯特联合肾脏病学研究所，南通大学附属医院肾内科，南通 226001；²南通大学附属医院临床医学研究中心，南通 226001；³莱斯特大学生命科学院心血管科学系肾脏研究组，莱斯特大学医院，莱斯特 LE1 9HN，英国

摘要

急性肾损伤(acute kidney injury, AKI)是以肾功能急剧衰退为主要表现的常见危重临床疾病。缺血再灌注(ischemia- reperfusion, IR)是AKI的主要病因之一。由于缺乏早期诊断方法和针对病因的特异性治疗，AKI的死亡率一直居高不下。IR快速诱发固有免疫反应，激活补体和固有免疫细胞，释放大量损伤相关分子如高迁移率族蛋白B1 (high mobility group box-1, HMGB1)、趋化因子及炎症介质如caspase-3，进而募集免疫炎症细胞如M1型巨噬细胞(Mϕ)至肾损伤微环境中，引起肾小管上皮细胞(tubular epithelial cells, TECs)坏死和凋亡。死亡细胞及相关炎症进一步激活适应性免疫系统，在加重组织损伤的同时，也启动了M2型Mϕ参与的炎症清除、组织再生及修复的程序。职业吞噬细胞Mϕ和半职业化吞噬细胞TECs协同吞噬周围的损伤细胞，包括凋亡的Mϕ及TECs，是调节损伤、修复或纤维化转归的关键固有免疫细胞。近年来研究发现促红细胞生成素(erythropoietin, EPO)不仅与同源二聚受体(EPOR)2结合诱导红细胞生成，还与异源二聚受体(EPOR/βcR)，亦称固有修复受体(innate repair receptor, IRR)，结合而发挥组织保护作用。备解素(properdin)是补体旁路激活过程中唯一的正性调节因子，能有效识别并结合早期凋亡T细胞，协助其通过非补体激活依赖机制被Mϕ清除。我们课题组的前期研究表明Mϕ、TECs、EPO及其受体和备解素等关联，参与IR损伤和修复，但其确切机制需要进一步研究。外泌体作为细胞间信号传递的重要载体，参与多种肾脏疾病的发生及发展，但其在IR诱导AKI的过程中如何影响Mϕ和TECs间互动尚未完全明确。本文根据已有关于Mϕ和TECs在肾IR所致AKI中作用的研究结果，进一步讨论Mϕ极化、与TECs互动以及EPO、备解素及外泌体在其中的作用。

关键词： 急性肾损伤; 促红细胞生成素受体; 外泌体; 缺血再灌注; 巨噬细胞; 备解素; 肾小管上皮细胞

The role of macrophage polarization and interaction with renal tubular epithelial cells in ischemia-reperfusion induced acute kidney injury

WANG Wei¹, SAI Wen-Li², YANG Bin^1,3,*

¹Nantong-Leicester Joint Institute of Kidney Science, Department of Nephrology, Affiliated Hospital of Nantong University, Nantong 226001, China；²Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China；³Renal Group, Department of Cardiovascular Sciences, University of Leicester, University Hospitals of Leicester, Leicester, LE1 9HN, UK

Abstract

Acute kidney injury (AKI) is a common critical clinical disease characterized by a sharp decline of renal function. Ischemia-reperfusion (IR) is one of the main causes of AKI. The mortality of AKI remains high due to the lack of early diagnosis and cause specific treatment. IR rapidly initiates innate immune responses, activates complement and innate immune cells, releasing a large number of injury-related molecules such as high mobility group box-1 (HMGB1), inflammatory mediators such as caspase-3, and then recruits immune inflammatory cells including M1 macrophages (Mϕ) to the microenvironment of injury, causing apoptosis and necrosis of renal tubular epithelial cells (TECs). Dead cells and associated inflammation further activate the adaptive immune system, which not only aggravates tissue damage, but also initiates M2 Mϕ participated inflammatory clearance, tissue repair and regeneration. Mϕ, professional phagocytes, and TECs, semi-professional phagocytes, can phagocytose around damaged cells including apoptotic Mϕ and TECs, which are key innate immune cells to regulate the outcome of injury, repair or fibrosis. In recent years, it has been found that erythropoietin (EPO) not only binds to the homodimeric receptor (EPOR)2 to induce erythropoiesis, but also binds to the heterodimeric receptor EPOR/βcR, also known as innate repair receptor, which plays renoprotective roles. Properdin is the only positive regulator in the complement activation of alternative pathway. It also can effectively identify and bind to early apoptotic T cells and facilitate phagocytic clearing by Mϕ through a non-complement activation-dependent mechanism. Our previous studies have shown that Mϕ and TECs associated with EPO and its receptors and properdin are involved in IR injury and repair, but the underlying mechanism needs to be further explored. As an important carrier of cell-to-cell signal transmission, exosomes participate in the occurrence and development of a variety of renal diseases. The role of exosomes involved in the interaction between Mϕ and TECs in IR-induced AKI is not fully defined. Based on the available results in the role of Mϕ and TECs in renal IR-induced AKI, this review discussed the role of Mϕ polarization and interaction with TECs in renal IR injury, as well as the participation of EPO and its receptors, properdin and exosomes.

Key words: acute kidney injury; erythropoietin receptor; exosome; ischemia-reperfusion; Macrophage; properdin; tubular epithelial cell

收稿日期：　　录用日期：

通讯作者：杨斌　　E-mail: by5@leicester.ac.uk, dryangbin@hotmail.com

DOI: 10.13294/j.aps.2022.0006

引用本文：

王薇, 赛文莉, 杨斌. 巨噬细胞极化及与肾小管上皮细胞互动在缺血再灌注所致急性肾损伤中的作用[J]. 生理学报 2022; 74 (1): 28-38.

WANG Wei, SAI Wen-Li, YANG Bin. The role of macrophage polarization and interaction with renal tubular epithelial cells in ischemia-reperfusion induced acute kidney injury. Acta Physiol Sin 2022; 74 (1): 28-38 (in Chinese with English abstract).