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Advances in Clinical Medicine
Vol. 14  No. 02 ( 2024 ), Article ID: 80419 , 5 pages
10.12677/ACM.2024.142332

白细胞介素-10在缺血性卒中中的作用

宋钊，高博涛*

西安医学院研究生院，陕西 西安

收稿日期：2024年1月1日；录用日期：2024年1月25日；发布日期：2024年2月2日

摘要

脑动脉闭塞后的缺血性卒中是造成全球慢性残疾的主要原因，也是全球第二大死亡原因。白细胞介素-10 (IL-10)是一种主要由Th2细胞和单核细胞分泌的免疫调节细胞因子。它对缺血性脑卒中的神经保护作用一直是研究热点。IL-10具有较强的免疫抑制活性。它可以抑制IL-2、IFN-g和促炎因子的产生和释放，降低免疫受体的表达，抑制人Th2细胞，导致细胞增殖，细胞因子产生减少。IL-10与IL-10受体(IL-10 R)结合以减少炎症并限制细胞凋亡。这些作用使其在脑缺血的保护中具有重要的作用。本文就IL-10在缺血性脑卒中中的多种作用作一综述。

关键词

缺血性卒中，白细胞介素-10，免疫细胞调节因子

The Role of Interleukin-10 in Ischemic Stroke

Zhao Song, Botao Gao*

Graduate School of Xi’an Medical University, Xi’an Shaanxi

Received: Jan. 1st, 2024; accepted: Jan. 25th, 2024; published: Feb. 2nd, 2024

ABSTRACT

Ischemic stroke following cerebral artery occlusion is the leading cause of chronic disability worldwide and the second leading cause of death worldwide. Interleukin-10 (IL-10) is an immunomodulatory cytokine secreted mainly by Th2 cells and monocytes. Its neuroprotective effect on ischemic stroke has been a focus of research. IL-10 has strong immunosuppressive activity. It can inhibit the production and release of IL-2, IFN-g and pro-inflammatory factors, reduce the expression of immune receptors, inhibit human Th2 cells, resulting in cell proliferation and reduced cytokine production. IL-10 binds to the IL-10 receptor (IL-10 R) to reduce inflammation and limit apoptosis. These effects make it play an important role in the protection of cerebral ischemia. This article reviews the various roles of IL-10 in ischemic stroke.

Keywords:Ischemic Stroke, IL-10, Immune Regulatory Cytokines

Copyright © 2024 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

脑动脉闭塞后的缺血性卒中是世界范围内慢性残疾的主要原因之一，仍然缺乏有效的方法来改善脑卒中后的功能恢复 [1] 。缺血性中风后，大脑供血严重不足导致大脑供氧不足，进而导致神经元死亡。脑毛细血管的血液–内皮界面处的炎症反应是缺血性组织损伤的基础。此外，血液–内皮界面的炎症相互作用，包括粘附分子、细胞因子、趋化因子和白色血细胞，对于脑梗死组织损伤的发病机制至关重要 [2] 。缺血性脑卒中后的病理生理变化包括离子失衡、神经炎症、免疫细胞异常激活等，可导致神经元死亡。然而，尽管已经进行了广泛的研究工作，但中风损伤的确切机制尚未完全了解。很明显，IL在缺血性卒中疾病的进展中起主要作用。

IL-10是一种重要的抗炎细胞因子，对多种免疫细胞具有抑制作用。IL-10首先在小鼠Th2细胞中鉴定，随后发现在星形胶质细胞、神经元、B细胞、单核细胞/巨噬细胞、角质形成细胞和人Th 1细胞中分泌。IL-10具有较强的免疫抑制活性。它可以抑制IL-2、IFN-g和促炎因子的产生和释放，降低免疫受体的表达，抑制人Th2细胞，导致细胞增殖，细胞因子产生减少 [3] 。IL-10与IL-10受体(IL-10 R)结合以减少炎症并限制细胞凋亡 [4] 。这些作用使其在脑缺血的保护中具有重要的作用。

2. IL-10与缺血性卒中

IL-10对缺血性脑卒中的神经保护作用一直是研究热点。一项探讨IL-10基因多态性与缺血性卒中风险之间关系的荟萃分析显示，IL-10与缺血性卒中风险总体上无显著相关性，但与大血管疾病和微血管疾病相关 [5] ，表明缺血性卒中的某些亚型与IL-10基因多态性相关。

在实验性中风中，IL-10 mRNA和蛋白以及IL-10 R mRNA水平升高，在缺血半暗带的小胶质细胞中观察到IL-10，在星形胶质细胞上观察到IL-10 R [6] 。在过度表达IL-10的转基因小鼠中，缺血性卒中后4天梗死面积减小，细胞凋亡有限 [7] 。此外，IL-10的过表达通过抗炎调节增强间充质干细胞移植的神经保护作用，从而支持急性缺血期间神经元的存活 [8] 。全身静脉(IV)和中枢脑室内(ICV)外源性给予IL-10均能减少永久性大脑中动脉闭塞(MCAO)后的梗死面积 [9] 。此外，低IL-10水平与不良卒中结局和延迟、加重的炎症反应相关，MCAO后IL-10给药可缓解炎症反应 [10] 。较低水平的IL-10和IL-33也可用于预测卒中后抑郁 [11] [12] 。IL-10在脑组织中的表达随着中枢神经系统的病理改变而增加，通过多种信号通路促进胶质细胞和神经元的存活，抑制炎症反应。

既往研究表明，IL-10的显著降低与神经功能缺损程度显著相关，IL-10浓度对急性脑卒中后早期神经行为表现具有较高的预测价值 [13] 。然而，由于卒中诱导的免疫抑制，卒中患者易感染，血清IL-10水平升高已被确定为卒中后感染的独立预测因子 [14] [15] 。IL-10过度反应可导致免疫抑制和卒中后神经系统预后恶化，表明应谨慎使用IL-10治疗 [16] 。IL-10水平升高可能与卒中后尿路感染的发生率较高相关，导致女性缺血性卒中后恢复较差 [17] [18] 。此外，IL-10可以介导Th2细胞的功能，发挥保护作用，并导致缺血性梗死病变的减少 [19] 。未来的研究应旨在区分脑卒中后中枢和外周IL-10的作用。

脑卒中发生后IL-10抑制炎症反应的机制

包括T和B细胞在内的免疫细胞可通过调节各种细胞因子和趋化因子来改善神经炎症，IL-10在其中发挥重要的免疫调节作用 [20] [21] 。IL-10对脑卒中的保护作用主要是通过抑制炎症反应来实现的。首先，IL-10通过激活PI 3 K和STAT 3降低促炎细胞因子如IFN-γ、IL-1b和TNF-α的表达和活性。其次，IL-10抑制Th 1淋巴细胞的合成和活性 [22] 。此外，IL-10治疗可有效下调卒中后急性缺血性病变中上调的促炎信号，并可为缺血性卒中提供神经保护 [23] 。脑动脉缺血前IL-10基因转导可通过增加血红素氧合酶的表达减轻大鼠缺血/再灌注引起的脑损伤 [24] 。IL-10还部分通过抑制NF-κ B发挥抗炎作用 [25] 。再灌注期间给予硫化氢供体可保护缺血/再灌注后BBB的完整性，并伴有IL-10表达增加、NF-κB核转位减少以及MMP-9和NOX 4活性降低 [26] 。在MCAO小鼠中，通过减少神经炎性因子(IL-6、IL-1b、TNF-α)的释放和星形胶质细胞活化，IL-32a过表达转基因小鼠显示缺血神经元的细胞死亡减少和抗神经炎性因子(IL-10)增强，表明IL-32a与IL-6、IL-1b、IL-10之间存在串扰 [27] 。鼻MOG诱导分泌IL-10的CD 4 + T细胞减少脑卒中后的损伤CD 4 + T细胞分泌的IL-10可能是MCAO小鼠给予少突胶质细胞糖蛋白的神经保护作用的原因 [28] [29] 。IL-10水平的增加也减少了CD 11b+细胞的数量，而CD 11b+细胞可能通过一氧化氮途径导致继发性梗死扩大 [29] 。在再灌注开始时通过给予CD 28超激动剂单克隆抗体扩增CNS Treg细胞群可减少MCAO后7天的梗死体积，其作用归因于IL-10增加 [30] 。在MCAO后24小时将产生IL-10的B细胞转移到B细胞缺陷小鼠中，可减轻脑缺血-再灌注损伤，减少脑实质中T细胞和单核细胞的数量，并改善外周促炎稳态。有趣的是，产生IL-10的B细胞也上调了T细胞的数量 [30] ，这表明B细胞和T细胞之间可能存在正反馈回路，两者都通过产生IL-10发挥神经保护作用。这些事实表明缺血性卒中中IL-10和免疫细胞之间存在复杂的网络。这些靶向IL-10以预防卒中复发的方法可以在卒中的介入治疗中实现。

3. L-10在缺血性脑卒中后神经再生中的作用

C57 BL/6小鼠短暂脑缺血60 min后侧脑室注射活化的调节性T细胞(Tregs)可促进缺血侧脑室下区神经干细胞的增殖。此外，用中和抗体阻断IL-10可消除这种作用，表明活化的Tregs通过IL-10促进神经干细胞的增殖 [31] 。造血细胞因子如GCSF和干细胞因子已被证实可促进神经发生 [32] ，也可能是缺血性卒中中IL-10产生的初始信号 [33] 。在C57 BL/6 J小鼠中，MCAO后早期(1~10天)和晚期(11~20天)给予这些细胞因子显著升高了IL-10的mRNA表达，减少了小胶质细胞/巨噬细胞的活化，并且没有改变促炎细胞因子水平 [33] 。在一项研究中，在MCAO前将骨髓间充质干细胞移植到Sprague-Dawley大鼠的侧脑室中，获得了类似的结果，其中IL-10 mRNA和蛋白水平在卒中后4天升高，TNFα降低，梗死面积较小，神经功能改善 [34] 。IL-10靶向巢蛋白(+)祖细胞，并通过调节成年脑室下区的ERK和STAT 3活性激活神经再生 [35] 。无论是干细胞本身的增值或造血细胞因子通过增加IL-10改善缺血性中风损伤部分。此外，生态失调后的神经保护依赖于IL-10和IL-17。Treg介导的IL-17(+)γδ T抑制需要IL-10 [36] 。最近，据报道IL-10对αβ和γδ T细胞的作用不同。产生IL-17 A的CD 4 (+)αβ T细胞通过其IL-10受体(IL-10 R)直接控制，而IL-10本身对γδ T细胞中的IL-17 A产生没有直接影响。γδ T细胞中IL-17 A产生的控制依赖于Tregs中完整的IL-10 R信号传导 [37] 。

文章引用

宋 钊,高博涛. 白细胞介素-10在缺血性卒中中的作用
The Role of Interleukin-10 in Ischemic Stroke[J]. 临床医学进展, 2024, 14(02): 2368-2372. https://doi.org/10.12677/ACM.2024.142332

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    38. NOTES

    *通讯作者。

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