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Advances in Clinical Medicine
Vol. 14  No. 02 ( 2024 ), Article ID: 82205 , 8 pages
10.12677/ACM.2024.142639

IL-33/ST2信号通路在aGVHD中的作用及 间充质干细胞干预的研究进展

申江艳，王洪波，江明*

新疆医科大学第一附属医院血液病一科，新疆 乌鲁木齐

收稿日期：2024年1月29日；录用日期：2024年2月23日；发布日期：2024年2月29日

摘要

急性移植物抗宿主病(acute Graft versus Host Disease, aGVHD)是异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT)后出现的严重并发症及死亡原因之一。aGVHD的发生十分复杂，许多机制尚未阐明。白细胞介素-33 (Interleukin 33, IL-33)及其受体白细胞介素1受体相关蛋白(Interleukin-1 receptor like-1，IL-1RL1，也称ST2)组成的信号通路除了参与感染性炎性疾病，自身免疫性疾病，变态反应性疾病，心血管疾病外，还参与aGVHD的发生。本文就IL-33及其受体ST2在免疫及aGVHD中的作用的研究进展进行综述，并对文献报道的aGVHD、间充质干细胞(mesenchymal stem cells, MSCs)及IL-33/ST2信号通路之间的相互作用进行梳理分析，期望为临床移植医学领域治疗aGVHD提供依据和方法。

关键词

白细胞介素-33，ST2，aGVHD，间充质干细胞

Research Progress on the Role of aGVHD and Its Mesenchymal Stem Cells Intervention in IL-33/ST2 Signaling Pathway

Jiangyan Shen, Hongbo Wang, Ming Jiang*

Department First of Hematology, First Affiliated Hospital of Xinjiang Medical University, Urumqi Xinjiang

Received: Jan. 29th, 2024; accepted: Feb. 23rd, 2024; published: Feb. 29th, 2024

ABSTRACT

Acute graft-versus-host disease (aGVHD) is one of the serious complications and causes of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The occurrence of aGVHD is complex and many mechanisms have not been elucidated. The signaling pathway composed of interleukin 33 (IL-33) and its receptor interleukin-1 receptor like-1 protein (IL-1RL1, also known as ST2) participates in the development of aGVHD, in addition to infectious inflammatory diseases, autoimmune diseases, allergic diseases, and cardiovascular diseases. This article reviews the research progress on the role of IL-33 and its receptor ST2 in immunity and aGVHD, and analyzes the effects of mesenchymal stem cells (MSCs) on the IL-33/ST2 signaling pathway reported in literature for the treatment of aGVHD. The aim is to provide a basis and method for the clinical treatment of aGVHD in the field of transplantation medicine.

Keywords:Interleukin-33, ST2, Acute Graft-Versus-Host Disease, Mesenchymal Stem Cells

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

异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT)是治疗高危血液恶性肿瘤的重要治疗手段，但严重和/或类固醇耐药的急性移植物抗宿主病(acute Graft Versus Host Disease, aGVHD)的发生、发展显著影响移植的最佳疗效且预后差，死亡率高。aGVHD的发生、发展是一个复杂的病理生理过程，细胞因子在其全程中起着至关重要的作用。抗原提呈细胞(antigen-presenting cells, APCs)活化：放化疗预处理造成组织损伤时释放的促炎细胞因子肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)、白细胞介素-6 (interleukin-6, IL-6)、警报蛋白如高迁移率族蛋白B1 (High mobility group box 1, HMGB1)、白细胞介素-1α (interleukin-1α, IL-1α)等增强宿主的APCs的抗原提呈能力。效应T细胞活化：供受者APCs及分泌的细胞因子一同活化下将供体T细胞扩增为效应T细胞。靶器官的损伤：活化的供体T细胞迁移到aGVHD的靶器官：肝脏、肠和皮肤等，释放大量促炎细胞因子如白细胞介素-2 (interleukin-2, IL-2)、干扰素-γ (interferon-γ, IFN-γ)、TNF-α，构成“细胞因子风暴”，攻击受者靶器官从而形成aGVHD特异性的病理损伤，组织的损伤可进一步活化T细胞，形成一个正反馈的恶性循环 [1] [2] 。aGVHD一旦发生就很难有效控制。皮质类固醇虽被视为GVHD的一线治疗 [3] ，但仍有高达50%的GVHD患者对此治疗没有完全反应 [4] 。且目前没有标准的二线治疗 [5] [6] 。因此，控制炎症因子风暴，下调机体的免疫应答，是治疗aGVHD的有效策略。

研究发现，IL-33也被认为是一种警报蛋白，其受体为白细胞介素1受体相关蛋白(Interleukin-1 receptor like-1，IL-1RL1，也称ST2)，两者组成的IL-33/ST2信号通路通过维持炎症和组织再生之间的平衡,促进损伤愈合和组织修复，在免疫性疾病中发挥关键作用 [7] ，大量研究发现它与aGVHD有关 [8] [9] 。间充质肝细胞(MSCs)在减轻炎症和自身免疫性疾病中发挥着重要作用。白细胞介素33 (IL-33)是IL-1家族的一员，已被证明可以调节先天免疫和适应性免疫。有研究表明IL-33可在促炎细胞因子刺激下由间充质干细胞产生，并通过驱动ST2 + Treg细胞的扩增发挥抗炎作用 [10] 。本文就IL-33、ST2的结构与功能及其在MSCs对aGVHD的作用进行简要综述。

2. IL-33/ST2的结构与功能

2.1. IL-33结构与功能

IL-33于1999年作为犬动脉中表达的蛋白质DVS27被首次发现 [11] ，后来被认定为次级淋巴器官中的“来自高内皮微静脉的核因子”(NF-HEV) [12] 。2005年，Schmitz等 [13] 将IL-33确定为一种新发现的细胞因子，属于IL-1家族的第11个成员，并发现ST2是其特异性受体。IL-33是由全长为270个氨基酸组成的蛋白质，由两个进化上保守的结构域组成。第一个结构域是N末端核结构域(氨基酸1-65)，为进化保守的同源结构域即螺旋–转角–螺旋结构域，可实现IL-33的核定位和染色质关联，起转录抑制作用 [14] [15] [16] 。第二个结构域是C末端IL-1样细胞因子结构域(氨基酸112-270)，为折叠的β三叶形结构，赋予IL-33的细胞因子样活性，释放到细胞外，参与调节Th2免疫反应 [14] [15] [16] 。在正常情况下，IL-33主要存在于内皮细胞、上皮细胞和其他细胞类型的细胞核内，参与染色质压缩和NF-κB转录活性的调节 [17] 。然而，当细胞受到压力或外界刺激时，IL-33释放，发挥多种生物功能。如：IL-33可以刺激肥大细胞、中性粒细胞、2型固有淋巴细胞(ILC2s)、原始T细胞以及其他免疫细胞分泌2型细胞因子IL4、IL-5和IL-13等介导2型免疫反应；增强Treg细胞免疫抑制功能；促进ILC2s产生双调节蛋白(Amphiregulin, AREG)用于组织修复 [18] [19] [20] 。另外，促炎细胞因子如IFN-γ [21] 、IL-4和IL-13 [22] 和Notch信号 [23] 增加IL-33的表达。

2.2. ST2结构与功能

IL-33受体ST2是IL-1受体(IL-1R)/Toll样受体(TLR)超家族的成员，由人类2号染色体上的IL-1RL1基因编码。目前发现的ST2有四种结构形式：可溶性ST2(sST2)、膜结合型ST2(ST2L)、可变型ST2(ST2V)、ST2L变异型(ST2LV)，其中最重要的与aGVHD相关的是ST2L和sST2。ST2L受体在多种造血细胞上表达，如Th2细胞、NK细胞、肥大细胞、单核/巨噬细胞和Tregs细胞 [24] [25] 。已观察到根据疾病类型不同这些类型细胞中的IL-33/ST2复合物信号通路具有促炎和抗炎反应。例如：IL-33通过诱导Th2细胞因子和促进选择性激活M2型巨噬细胞极化，对多种心血管疾病具有保护作用，发挥抗炎反应 [26] 。IL-33还具有促炎作用，可导致哮喘、过敏性反应和特应性皮炎的发生 [26] 。IL-33受体ST2被鉴定为成纤维细胞产生的mRNA。sST2受体由单个mRNA通过两个不同启动子的差异表达和选择性剪接产生 [25] [27] 。sST2的释放需要血管充血、炎症和促纤维化的刺激 [28] 。sST2作为IL-33诱捕受体 [29] ，由肺、肾、心脏和小肠中的内皮细胞、上皮细胞、成纤维细胞和T细胞中产生，在炎症过程中其产生增加，其中sST2也由免疫细胞产生 [29] [30] [31] 。sST2结构与ST2L的胞外段相同，但其C端特有9个氨基酸，促Th2细胞向Th1细胞漂移，抑制Th2免疫应答 [32] 。

2.3. IL-33/ST2信号通路

细胞外IL-33通过受体ST2及其辅助受体IL-1受体辅助蛋白(IL-1RacP，也称为IL1-R3)发挥其功能。IL-33与ST2L的结合使其能够与IL-1RacP形成异二聚体复合物，IL-33与受体复合物的结合招募下游适配器分子，包括髓样分化因子88 (MyD88)、IL-1受体相关激酶1 (IRAK1)、IRAK4和TNF受体相关因子6 (TRAF6)，激活磷脂酶D-鞘氨醇激酶(PLD-SPHK)途径，诱导活化核因子κB (NF-κB)和丝裂原激活蛋白激酶(MAPK)途径，而MAPK途径决定了细胞外信号调节激酶(ERK)、Jun N末端激酶(JNK)和p38的激活。两途径通过相互协同作用诱导基因表达调节Th2型应答相关的细胞因子的转录，从而促进炎症介质产生，发挥炎症及免疫调节作用 [17] [32] [33] [34] 。血清sST2则作为诱骗受体，直接结合IL-33，抑制IL-33的活性，促使Th2细胞向 Th1细胞漂移，抑制Th2免疫应答，阻断炎症的发生 [35] 。IL-33/ST2可促进CD8毒性T淋巴细胞和Th1细胞的扩增，从而介导保护性抗病毒反应 [36] 。

3. IL-33/ST2在aGVHD中的作用

3.1. IL-33在aGVHD中的作用

aGVHD发生的经典途径包括靶器官的损伤如肠道、皮肤、肝脏，其次是细胞因子风暴的释放，增加供者的免疫细胞识别宿主的同种异体抗原的机会 [37] 。组织损伤相关IL-33释放的一个重要作用是通过抗炎性Treg细胞的扩增来建立免疫耐受，从而参与炎症介导的组织修复。IL-33激活下游信号发挥作用，需要MyD88的参与。Matsuoka等 [38] 证明T细胞中的MyD88信号是供体T细胞存活和Th1、Tc1和Th17分化所必需的，从而导致致死性的GVHD。供体T细胞中MyD88的缺乏也促进同种allo-HSCT后Foxp3 + Treg的扩增，以降低GVHD的致死率。IL-33被认为主要作为抗原提呈细胞(APC)产生的IL-12的佐剂，APC将供体T细胞推向GVHD中炎症Th1谱系 [39] 。Dwyer等 [8] 报告了他们使用小鼠GVHD模型，以证明IL-33直接作用于供体T细胞，从而独立于IL-12增加Tbet表达。坚定地确立了IL-33是GVHD期间Th1细胞的重要共刺激分子，并为减少GVHD提供了靶点，特别是在胃肠道损伤时导致死亡。Matta等 [40] 发现在allo-HSCT后使用IL-33会加剧GVHD，但在allo-HSCT预处理前给予IL-33会增加ST2 + Tregs的数量，这些IL-33扩增的Tregs调节髓样细胞的分化和活化，并限制GVHD靶组织中效应T细胞的积累来保护受体免受GVHD的影响。关于IL-33对aGVHD的影响，目前尚无统一定论。

3.2. ST2在aGVHD中的作用

sST2首次被确认为预测类固醇耐药aGVHD的血清生物标志物 [41] 。Cantilena等 [42] 认为sST2水平明显升高的患者其移植后早期发生 GVHD的风险明显增加。故早期检测sST2有助于aGVHD的诊断。Griesenauer等 [43] 通过对小鼠异基因造血细胞移植模型的研究，发现供体MyD88缺失的常规T细胞(conventional T cells, Tcons)降低sST2的产生，保护小鼠免受致命的aGVHD，同时也保留了Treg功能。并认为sST2代表了一个潜在的aGVHD治疗靶点，而不是Tregs。在发生GVHD的allo-HSCT患者中，观察到sST2水平升高，是一个重要的预后生物标志物 [44] 。对于这些患者，过量的sST2会抵消IL-33，从而抑制免疫耐受，导致GVHD进展中的不平衡和明显的促炎性免疫反应 [45] 。Reichenbach等 [46] 通过GVHD小鼠模型研究，考虑到sST2作为诱饵受体的功能，可隔离游离的IL-33，因此，外源性给药隔离IL-33的sST2-Fc融合蛋白可改善某些临床前模型中的GVHD [47] 。Zhang等人 [48] 通过GVHD模型表示，在GVHD期间，ST2阻断剂可减少产生sST2的T细胞，同时维持保护性mST2表达的T细胞。sST2的短暂阻断增加了Th2转录因子GATA3和细胞因子IL-4，改善了Th2表型，从而预防严重GVHD。sST2水平升高是接受allo-HSCT患者GVHD和死亡的风险生物标志物，这一发现也强调了IL-33在GVHD中的重要性。

4. MSCs、aGVHD与IL-33

4.1. MSCs与aGVHD

作为急性移植物抗宿主病(aGVHD)的一线治疗主要药物，全身性类固醇增加了感染的风险 [49] ，类固醇难治性aGVHD (SR-aGVHD)的预后较差，2年总生存率为25% [50] 。因此，寻找新的可行性的治疗方法预防严重和SR-aGVHD对提高生存率至关重要。研究表明，间充质干细胞(MSCs)具有免疫调节特性，不受HLA低表达宿主–受体匹配的影响。被认为是一种具有良好临床前景的治疗方法。间充质干细胞也称间充质基质细胞，是一类主要起源于中胚层的祖细胞，具有自我更新及分化潜能，最早于上世纪中叶在骨髓中发现 [51] ，如今，许多组织中都发现了间充质干细胞，例如脂肪组织，胎盘与脐带，他们已被用作骨髓间充质干细胞的替代来源 [52] [53] 。其中脂肪间充质干细胞(adipose derived stem cells, ADSCs)由于获取方式方便，细胞增殖迅速，免疫调控能力强格外被青睐。ADSCs属于成体干细胞的一种，于2001年Zuk等人在脂肪组织的培养中发现了一组梭形贴壁生长的、具有干细胞特性的细胞群并首次从人体脂肪组织中分离获得，是目前国际公认的优势干细胞 [54] 。大量研究表明，ADSCs的成脂、成骨和成软骨能力在多种组织修复中有巨大的应用，而其低免疫原性和免疫调控能力可以降低细胞移植中的免疫排异反应 [55] 。

据报道，ADSCs在治疗和预防allo-HSCT引起的aGVHD最为有益 [56] 。已有研究表明ADSCs发挥免疫调节功能主要与T细胞亚群相关。ADSC可通过下调Th1细胞(转录因子T-bet表达减低)分化，上调Th2细胞(转录因子GATA3表达升高)分化，促进Th1/Th2 亚群平衡来治疗aGVHD [57] 。ADSCs对自然杀伤(NK)细胞的增殖和功能的不良影响较小，因此可以保留更多的GVL效应 [58] 。在抑制T细胞免疫的同时保留NK细胞反应的策略可能有利于GVL和GVHD之间的正平衡 [58] 。是否有其他机制在ADSC中发挥免疫调节作用有待研究。

4.2. MSCs表达IL-33

Chen等 [59] 通过对急性心肌梗死SD大鼠模型的研究表明，骨髓间充质干细胞过度表达IL-33通过增强巨噬细胞向M2的极化，增强CD4+ T细胞向CD4 + IL4 + Th2细胞的分化，最终减轻心脏炎症，增强心脏功能，从而增强MSCs对急性心肌梗死的免疫调节功能和治疗作用。而Martínez-González等 [60] 通过对小鼠急性肺损伤(ALI)模型研究表明，人脂肪源间充质干细胞(hADSCs)过度表达IL-33拮抗剂sST2可减轻内毒素诱导的ALI，且经hADSCs-sST2治疗ALI的肺表现出肺泡结构的完整，无细胞凋亡，炎症细胞浸润最小的优点，有望成为治疗ALI/ARDS(急性呼吸窘迫综合征)的一种有前景的策略。Liu 等 [10] 通过对NOD小鼠Sjögren综合征模型研究显示，依赖于TAK1、ERK和p38通路，小鼠脂肪源间充质干细胞(mADSCs)在IL-1β刺激下产生IL-33，且呈现浓度依赖性即在一定范围内IL-1β浓度越高产生的IL-33越多。mADSCs产生的IL-33可促进CD4 + Foxp3 + ST2 + Tregs增值，并抑制NOD小鼠唾液腺炎症减轻小鼠实验性自身免疫性干燥综合征。hADSCs也通过TAK1-ERK/p38信号通路在IL-1β刺激产生IL-33。尽管仍需在临床患者中得到证实，但动物实验相关证据确实表明了动物研究的临床相关性。

5. 小结与展望

严重和SR-aGVHD预后差且死亡率高，因此需要新的治疗方法，越来越多的研究表明MSCs对aGVHD存在治疗作用，而IL-33/ST2是可能发挥重要作用的通路。目前关于MSCs对aGVHD的治疗作用IL-33/ST2信号通路在其中的确切功能和潜在机制，还有很多尚待阐明且尚无定论。需要不断对MSCs治疗aGVHD中IL-33/ST2信号通路的功能、作用机制、免疫调控方面进行更深入的研究。

利益冲突

所有作者声明无利益冲突。

作者贡献声明

申江艳：文章撰写；王洪波：文献资料梳理；江明：研究指导、论文审阅、经费支持。

基金项目

新疆维吾尔自治区自然科学基金重点项目(2022D01D62)。

文章引用

申江艳,王洪波,江 明. IL-33/ST2信号通路在aGVHD中的作用及间充质干细胞干预的研究进展
Research Progress on the Role of aGVHD and Its Mesenchymal Stem Cells Intervention in IL-33/ST2 Signaling Pathway[J]. 临床医学进展, 2024, 14(02): 4604-4611. https://doi.org/10.12677/ACM.2024.142639

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    61. NOTES

    *通讯作者。

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