药学学报

Source	Mechanism	Effect
Podocytes	●Inflammatory exosomes mediate inflammatory responses by carrying NLRP3 inflammasome products^[59]	●Promote glomerular inflammation
CMECs	●GEC1 autophagosomes are released through exosomes and generate a large number of NLRP3 inflammasomes, stimulating an increase in monocytes and neutrophils^[105]	●Trigger vascular inflammation
Saliva	●MiR-223-3p regulates GSDMD-mediated pyroptosis in periodontitis by targeting NLRP3^[106]	●Relieve inflammation
Plasma	●Plasma derived exosomes from COVID-19 patients triggered NLRP3 inflammasome in endothelial cells of distal organs, leading to IL-1β secretion^[107]	●Promote inflammation
HUVECs	●NEAT1 delivery via DDX3X/NLRP3 regulatory axis increased the infiltration of M2-polarized macrophages and decreased NLRP3 expression^[108]	●Relieve inflammation

Source

Mechanism

Effect

Podocytes

●Inflammatory exosomes mediate inflammatory responses by carrying NLRP3 inflammasome products^[59]

●Promote glomerular inflammation

CMECs

●GEC1 autophagosomes are released through exosomes and generate a large number of NLRP3 inflammasomes, stimulating an increase in monocytes and neutrophils^[105]

●Trigger vascular inflammation

Saliva

●MiR-223-3p regulates GSDMD-mediated pyroptosis in periodontitis by targeting NLRP3^[106]

●Relieve inflammation

Plasma

●Plasma derived exosomes from COVID-19 patients triggered NLRP3 inflammasome in endothelial cells of distal organs, leading to IL-1β secretion^[107]

●Promote inflammation

HUVECs

●NEAT1 delivery via DDX3X/NLRP3 regulatory axis increased the infiltration of M2-polarized macrophages and decreased NLRP3 expression^[108]

●Relieve inflammation

Source	Mechanism	Effect
Podocytes	●Inflammatory exosomes mediate inflammatory responses by carrying NLRP3 inflammasome products^[59]	●Promote glomerular inflammation
CMECs	●GEC1 autophagosomes are released through exosomes and generate a large number of NLRP3 inflammasomes, stimulating an increase in monocytes and neutrophils^[105]	●Trigger vascular inflammation
Saliva	●MiR-223-3p regulates GSDMD-mediated pyroptosis in periodontitis by targeting NLRP3^[106]	●Relieve inflammation
Plasma	●Plasma derived exosomes from COVID-19 patients triggered NLRP3 inflammasome in endothelial cells of distal organs, leading to IL-1β secretion^[107]	●Promote inflammation
HUVECs	●NEAT1 delivery via DDX3X/NLRP3 regulatory axis increased the infiltration of M2-polarized macrophages and decreased NLRP3 expression^[108]	●Relieve inflammation

Source

Mechanism

Effect

Podocytes

●Inflammatory exosomes mediate inflammatory responses by carrying NLRP3 inflammasome products^[59]

●Promote glomerular inflammation

CMECs

●GEC1 autophagosomes are released through exosomes and generate a large number of NLRP3 inflammasomes, stimulating an increase in monocytes and neutrophils^[105]

●Trigger vascular inflammation

Saliva

●MiR-223-3p regulates GSDMD-mediated pyroptosis in periodontitis by targeting NLRP3^[106]

●Relieve inflammation

Plasma

●Plasma derived exosomes from COVID-19 patients triggered NLRP3 inflammasome in endothelial cells of distal organs, leading to IL-1β secretion^[107]

●Promote inflammation

HUVECs

●NEAT1 delivery via DDX3X/NLRP3 regulatory axis increased the infiltration of M2-polarized macrophages and decreased NLRP3 expression^[108]

●Relieve inflammation

外泌体对NLRP3炎症小体调控作用的研究进展

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李美伶 , 徐明 ^*

药学学报 | 综述 2025,60(4): 853-863

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药学学报 | 综述 2025, 60(4): 853-863

外泌体对NLRP3炎症小体调控作用的研究进展

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李美伶, 徐明^*

作者信息

中国药科大学基础医学与临床药学学院, 江苏南京 210009

通讯作者:

徐明, Tel: 15805195696, E-mail: mingxu2016@163.com

Advances in the regulatory effects of exosomes on NLRP3 inflammasome

Mei-ling LI, Ming XU^*

Affiliations

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China

出版时间: 2025-04-12 doi: 10.16438/j.0513-4870.2024-0909

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摘要

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外泌体是一种由细胞分泌的含有核酸和蛋白质等重要生物活性分子的小囊泡。越来越多的研究表明, 外泌体作为信号分子载体在各种疾病中具有独特和关键的作用, 并且在疾病诊断和治疗方面展现出巨大潜力。最近研究表明外泌体在免疫调控中发挥着重要作用。NOD (nucleotide binding oligomerization domain) 样受体家族3 (NOD-like receptor protein 3, NLRP3) 炎症小体是固有免疫系统的重要组成部分, 在自身免疫性疾病、代谢性疾病及神经退行性疾病等多种疾病的发生、发展中发挥关键作用, 其激活和调控机制复杂多样。然而, 外泌体和NLRP3炎症小体相关的调控机制尚未完全阐明。本文综述了不同来源的外泌体对NLRP3炎症小体的调控作用, 并总结了外泌体在NLRP3炎症小体相关疾病的治疗潜力, 以期为NLRP3炎症小体相关疾病的防治提供新思路。

关键词

外泌体 / 炎症 / 免疫调控 / NLRP3炎症小体 / 疾病治疗

Abstract

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Exosomes are small vesicles secreted by cells that contain important bioactive molecules such as nucleic acids and proteins. Increasing research indicates that exosomes play a unique and crucial role as signal molecule carriers in various diseases, and they exhibit great potential in disease diagnosis and treatment. Recent studies have shown that exosomes play an important role in immune regulation. The NOD (nucleotide binding oligomerization domain)-like receptors protein 3 (NLRP3), an essential component of the innate immune system, plays a key role in the occurrence and development of various diseases including autoimmune diseases, metabolic diseases, and neurodegenerative diseases. Its activation and regulatory mechanisms are complex and diverse. However, the regulatory mechanisms associated with exosomes and NLRP3 inflammasome have not yet been fully elucidated. This article reviews the regulatory effects of exosomes from different sources on the NLRP3 inflammasome and summarizes the therapeutic potential of exosomes in diseases associated with the NLRP3 inflammasome, aiming to provide new ideas for the prevention and treatment of diseases related to the NLRP3 inflammasome.

Key words

exosome / inflammation / immune regulation / NLRP3 inflammasome / disease treatment

引用本文

李美伶, 徐明. 外泌体对NLRP3炎症小体调控作用的研究进展. 药学学报, 2025 , 60 (4) : 853 -863 . DOI: 10.16438/j.0513-4870.2024-0909

Mei-ling LI, Ming XU. Advances in the regulatory effects of exosomes on NLRP3 inflammasome[J]. Acta Pharmaceutica Sinica, 2025 , 60 (4) : 853 -863 . DOI: 10.16438/j.0513-4870.2024-0909

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外泌体是细胞分泌到胞外的一种囊泡, 其大小介于30~150 nm之间, 具有双层膜结构和茶托状形态, 内部富含多种生物活性物质, 包括核酸、蛋白质及脂质等。与游离的生物分子相比, 外泌体内部的这些分子因其包裹作用而展现出更高的稳定性与生物相容性特性^[1]。外泌体来源于细胞内溶酶体微粒内陷形成的多囊泡体, 经多囊泡体外膜与细胞膜融合后释放到胞外基质中。它们广泛分布于各种体液中, 包括心包积液、尿液、羊水、唾液、脑脊液、腹水和血液^{[2, 3]}。作为细胞间信息传递的关键媒介, 外泌体形成了一种全新的细胞与细胞之间的信息传递系统, 可参与细胞通讯、细胞迁移、血管新生和肿瘤细胞生长等过程^[4]。外泌体包含多种与膜运输和融合相关的蛋白质, 如Ras相关结合蛋白GTP酶、膜连蛋白、整合素和纤维连接蛋白^{[5, 6]}, 以及CD9、CD63、CD81和CD82等四跨膜蛋白^[7], 热休克蛋白^[8]和脂质筏蛋白^[9]。很多种细胞都可以分泌外泌体, 包括干细胞^[10-12]、免疫细胞^[13]、肿瘤细胞^{[14, 15]}、神经细胞^{[16, 17]}等。外泌体中的细胞特异性蛋白和遗传物质可以反映其起源细胞的特性及其生理状态, 不同类型的细胞分泌的外泌体具有不同的组成成分和功能^[18]。

自1983年首次发现外泌体以来, 其分子机制和功能得到了越来越多的探索^[19]。据报道, 外泌体在癌症进展、心血管疾病、肝纤维化、非酒精性脂肪性肝炎和代谢性疾病中具有重大影响^[20-24]。外泌体还可作为疾病生物标志物, 为胃癌、乳腺癌、前列腺癌等癌症的早期诊断提供依据^[25-27]。目前, 越来越多的研究关注外泌体与疾病进展中的免疫调节机制之间的关联^[28]。如肿瘤细胞分泌的外泌体已在某些癌症类型中用于调节免疫反应^[29]。新兴研究已确认外泌体可以增强巨噬细胞的吞噬作用、调节抗原呈递, 并诱导免疫激活和免疫抑制^[30]。

炎症小体的组成包括模式识别受体(pattern recognition receptor, PRR)、凋亡相关斑点样蛋白(apoptosis-associated speck-like protein containing a caspase-recruitment domain, ASC) 及半胱天冬氨酸蛋白水解酶1前体(pro-cysteinyl aspartate specific proteinase 1, pro-caspase-1)^[31]。迄今为止, 已发现5种能够形成炎症小体的PRRs, 包括NOD (nucleotide binding oligomerization domain) 样受体家族(NOD-like receptors protein, NLRP) 1、NLRP3、NLR家族含有半胱天冬酶募集结构域蛋白4 (NLR family caspase recruitment domain-containing protein 4, NLRC4)、Pyrin和黑色素瘤2缺乏双链DNA传感器(double-stranded DNA sensors absent in melanoma 2, AIM2)。而其中的NLRP3炎症小体是目前研究最为深入的炎症小体^[32]。NLRP3炎症小体是一种胞浆多蛋白复合物, 由一个传感器(NLRP3蛋白)、一个接头蛋白(ASC) 和一个效应器(caspase-1) 组成。

NLRP3炎症小体主要介导宿主对微生物感染和细胞损伤的免疫反应, 参与多种炎症相关疾病的发生和发展, 如2型糖尿病^[33]、痛风^{[34, 35]}、动脉粥样硬化^[36]、神经退行性疾病^[37]、肿瘤^[38]、炎症性肠病^[39]等。

1 外泌体与NLRP3炎症小体激活

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研究表明, NLRP3炎症小体可以通过3种不同的信号通路激活: 经典的NLRP3炎症小体激活、非经典的NLRP3炎症小体激活和替代的NLRP3炎症小体激活。经典的NLRP3炎症小体的完全激活需要两个连续信号: 第一个是启动信号, 第二个是组装信号。在启动阶段, Toll样受体(toll like receptor) 如TLR2和TLR4的配体、细胞因子受体的配体如白细胞介素(interleukin, IL)-1和肿瘤坏死因子-α (tumor necrosis factor-alpha, TNF-α) 或NLR如核苷酸结合寡聚化结构域蛋白(nucleotide-binding oligomerization domain containing protein, NOD) 1和NOD2的配体如胞壁酰二肽(muramyl dipeptide, MDP) 可以诱导NF-κB (nuclear factor kappa B) 信号通路的激活, 并促进NLRP3和白细胞介素-1β前体(pro-interleukin-1β, pro-IL-1β) 的表达^[40-43]。在启动阶段之后, NLRP3炎症小体需要额外的信号来完成其激活。这些信号包括细胞外三磷酸腺苷(adenosine triphosphate, ATP)、线粒体活性氧(reactive oxygen species, ROS)、溶酶体损伤释放的组织蛋白酶B (cathesin B)、K⁺外流等。在组装阶段, NLRP3结合在内质网相关的线粒体膜上, 并被氧化的线粒体DNA (oxidized mitochondrial DNA, ox-mtDNA) 激活^[44]。活化的NLRP3被转运到分散的反式高尔基体上^[45], 组装成寡聚体的双环笼结构^[46]。随后NLRP3被再次转运到微管组织中心^[47], 与丝氨酸/苏氨酸蛋白激酶7 [(never in mitosis gene A)-related kinase 7, NEK7] 结合从而稳定寡聚体。NEK7是NLRP3炎症小体激活和组装的重要调节因子, NEK7与NLRP3的结合破坏了NLRP3双环结构并导致结构重排, 暴露PYD结构域(pyrin domain) 并允许NACHT结构域(nucleoside triphosphatase domain) 寡聚化。当NACHT结构域被ATP交换和NEK7结合激活后, PYD结构域通过PYD-PYD结构域相互作用招募接头分子ASC形成丝状结构, 起始炎症小体的组装, 促进下游细胞因子的加工和释放^[48]。ASC作为接头蛋白, 一端与NLRP3的PYD结构域结合, 另一端与pro-caspase-1的CARD结构域(caspase recruitment domain) 结合。随着ASC的桥接作用, caspase-1前体聚集并自我剪切, 形成活性的caspase-1酶。活性caspase-1能够切割其底物, 包括pro-IL-1β和白细胞介素-18前体(pro-interleukin-18, pro-IL-18), 产生具有生物活性的IL-1β和IL-18, 这两种细胞因子对于启动和放大炎症反应至关重要。活化的caspase-1会裂解gasdermin D (GSDMD) 并释放其N端结构域, 该结构域转移到细胞膜并形成跨膜孔洞, 介导细胞内容物的释放, 包括炎症细胞因子IL-1β和IL-18, 并诱导细胞焦亡^[49]。

除经典途径外, NLRP3炎症小体的激活还可通过非经典途径实现。非经典NLRP3炎性小体激活是由LPS启动的, 小鼠体内的caspase-11 (或人体内的caspase-4和caspase-5) 可通过直接相互作用识别, 导致caspase-11自身蛋白水解和激活。然后, 激活的caspase-11打开膜联蛋白-1 (pannexin-1) 通道, 诱导K⁺外排, 导致经典的NLRP3炎症小体活化及IL-1β和IL-18成熟。同时, 激活的caspase-11也会裂解GSDMD, 诱导膜孔形成和焦亡, 从而促进IL-1β和IL-18的释放^{[50, 51]}。来自北京大学的研究团队发现在LPS的刺激下孤儿核受体蛋白Nur77结合LPS和从线粒体膜上的GSDMD孔释放的线粒体DNA, 随后Nur77结合NLRP3并促进NLRP3炎症小体的低聚和活化。Nur77连接了caspase-11的激活和下游NLRP3炎症小体的形成, 并可能成为炎症性疾病和脓毒症治疗的一个靶点^[52]。

替代性NLRP3炎症小体激活只需要一个信号。仅TLR配体就可以通过TLR4-含有TIR结构域的诱导干扰素β的适配蛋白(TIR domain-containing adaptor protein-inducing interferon β, TRIF)-受体相互作用的丝氨酸/苏氨酸蛋白激酶1 (receptor-interacting serine/threonine-protein kinase 1, RIPK1)-Fas相关的死亡结构域蛋白(Fas-associated death domain protein, FADD)-半胱氨酸天冬氨酸蛋白酶8 (cysteine-aspartic acid protease 8, CASP8) 信号轴激活人和猪单核细胞中的NLRP3炎症小体, 而不需要诱导K⁺外排、ASC斑点形成或焦亡^{[53, 54]}。

NLRP3炎症小体在炎症性疾病中起着关键作用^[55]。而外泌体在免疫调节中有着重要的作用^{[56, 57]}。越来越多的证据表明, 外泌体可以通过NLRP3炎症小体的激活途径参与疾病的发生和发展。值得注意的是, 基于现有证据, 外泌体被证明对炎症小体激活具有双重作用。因此, 更好地理解外泌体与NLRP3炎症小体激活之间的关系可能在揭示治疗NLRP3炎症小体相关疾病的潜在靶点上起重要作用。

近年来已有不少研究证据表明, 外泌体可以通过分泌不同物质影响经典NLRP3炎症小体激活通路中的关键分子, 进而影响与NLRP3炎症小体相关的疾病过程^[58-61]。外泌体可以通过携带特定的miRNA以不同的途径来抑制NLRP3炎症小体的激活, 从而减少炎症反应。有研究发现, miR-148a能够增强细胞活性, 并缓解缺血/再灌注引起的新生大鼠心肌细胞中的酶失调和Ca²⁺过载。M2型巨噬细胞衍生的外泌体携带miR-148a, 可以直接靶向硫氧还蛋白相互作用蛋白(thioredoxin-interacting protein, TXNIP) 并显著抑制其表达, 从而显著抑制TLR4的表达。下游的NF-κB激活和NLRP3炎症小体组分的表达被明显抑制, 这有助于减轻心肌缺血/再灌注损伤^[62]。在肺巨噬细胞介导的炎症反应中, 外泌体miR-223/142分泌显著增强, 且在支气管肺泡灌洗液和血清中均可检测到。通过外泌体介导的途径恢复细胞内miR-223/142能够抑制NLRP3炎症小体的激活, 从而抑制巨噬细胞活化和肺部炎症^[63]。此外, 有研究报道, 脐带MSC-Exos中的环状同源域相互作用蛋白激酶3 (circHIPK3) 可以下调miR-421, 导致叉头框转录因子O3a (forkhead-box O3a, FOXO3a) 的高表达, 从而抑制NLRP3炎症小体的激活, 阻止细胞焦亡并修复缺血性肌肉损伤^[58]。在预防术后心房颤动的研究中发现, 心脏来源的外泌体能够直接作用于心房成纤维细胞和巨噬细胞, 抑制NLRP3炎症小体的激活。这种抑制作用与外泌体剂量有关, 随着剂量增加, 抑制效果更加显著^[64]。这些证据表明, 外泌体能够通过多种机制抑制NLRP3炎症小体的激活, 包括抑制NF-κB的核转位、降低促炎细胞因子的表达、调节自噬过程、直接作用于心房成纤维细胞和巨噬细胞, 以及减少氧化应激和炎症浸润等。

2 干细胞来源的外泌体通过不同的途径抑制NLRP3炎症小体的活化

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间充质干细胞(mesenchymal stem cells, MSC) 源自中胚层, 具备自我更新和多向分化的潜能。近年来, 由于其再生能力和免疫抑制特性^[65-67], 推动了MSC在多种疾病治疗中的临床试验应用^{[68, 69]}。MSC可以从多种组织如骨髓、脂肪、脐带和脐血等提取, 并具有良好的体外增殖能力, 这极大促进了其应用^[70]。

MSC能够通过分泌外泌体来发挥治疗作用。作为外泌体的来源, MSC具有两个显著特征: 即免疫调节特性和低生产成本。MSC的免疫调节作用是其独特能力之一, 研究表明, 部分免疫调节特性能传递到它们产生的外泌体中^{[71, 72]}。MSC来源的外泌体可以调控固有免疫与适应性免疫应答, 通过抑制T淋巴细胞功能、降低B细胞活化、增殖与分泌、影响巨噬细胞分化与树突状细胞成熟以及抑制自然杀伤细胞的细胞毒活性来发挥免疫调控作用^[73], 从而提高MSC外泌体衍生药物递送载体的寿命和药物的生物利用度。此外, 越来越多的证据显示, 与其他细胞相比, MSC能产生更大量的外泌体^[11], 所以用MSC产生外泌体能降低外泌体的生产成本。MSC来源的外泌体能通过不同的途径和机制抑制或减少NLRP3炎症小体的活化。

2.1 间充质干细胞来源的外泌体抑制细胞焦亡

细胞焦亡是一种细胞死亡过程, 其特征是炎症性细胞因子的过度释放, 与NLRP3-GSDMD通路密切相关。在缺血/再灌注损伤模型中, NLRP3、caspase-1和GSDMD表达水平显著增加^[74]。线粒体功能障碍和ROS的积累在缺血再灌注相关的NLRP3激活中至关重要^{[75, 76]}。

研究发现, 人类骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSC) 衍生的外泌体可以显著抑制缺血再灌注心肌中的NLRP3表达。其机制是BMSC来源的外泌体miR-320b直接靶向NLRP3分子, 然后负向调控下游caspase-1的表达, 从而在大鼠心肌缺血再灌注模型中抑制焦亡^[77]。此外, 有研究表明, 人脐带间充质干细胞(human umbilical cord mesenchymal stem cells, hucMSC) 来源的外泌体能够抑制小鼠结肠中NLRP3炎症小体的活化, 并延缓细胞焦亡, 从而促进巨噬细胞的增殖, 改善炎症性肠病。其作用机制可能是miR-378a-5p/NLRP3轴^[78]。hucMSC来源的外泌体还可以通过甲基转移酶催化m6A修饰, 靶向甲基转移酶样蛋白14 (methyltransferase-like 14, METTL14), 有效提高髓核细胞的生存能力, 保护髓核细胞免于焦亡。METTL14在椎间盘退变患者髓核细胞中高表达, 通过胰岛素样生长因子结合蛋白2依赖的方式稳定NLRP3 mRNA的表达。NLRP3水平升高导致IL-1β和IL-18水平升高, 触发焦亡性髓核细胞死亡。hucMSC外泌体可通过外泌体miR-26a-5p直接降解METTL14, 从而阻断这一致病轴^[79]。在神经保护方面, 人脐带MSC外泌体通过减少NLRP3的表达和上调FOXO3a来增强线粒体自噬, 从而保护小胶质细胞免受缺血/再灌注诱导的焦亡, 减轻随后的神经元损伤^[80]。

在体内动物实验中, 骨髓间充质干细胞来源的外泌体(bone marrow mesenchymal stem cells-derived exosomes, BMSC-Exos) 能够下调NLRP3炎症小体和焦亡相关蛋白的表达。此外, BMSC-Exos可使脑缺血再灌注损伤诱导的M1型小胶质细胞向M2型转化。在体外实验中, BMSC-Exos通过调节小胶质细胞极化, 抑制NLRP3炎症小体介导的炎症反应和细胞焦亡, 从而减轻脑缺血再灌注损伤^[81]。

多柔比星诱导的心脏毒性是通过氧化应激、细胞凋亡和坏死增加来介导的, 而胚胎干细胞来源的外泌体可抑制多柔比星诱导的细胞焦亡。因此, 外泌体可作为未来治疗多柔比星诱导的心脏毒性的一种选择^[82]。

2.2 干细胞来源的外泌体促进细胞自噬

自噬是真核生物细胞在遭遇各种应激压力时发生的一种进化上高度保守的代谢途径, 主要参与细胞内物质的周转过程。这一过程通过形成双层膜结构的自噬小泡, 将损坏的蛋白质或细胞器以及胞内病原体包裹起来, 然后送入溶酶体或液泡中进行降解^[83]。自噬不仅在维持细胞稳态和循环营养物质方面发挥重要作用, 还与多种生理和病理过程密切相关, 对预防与治疗人类重大疾病具有重要意义。自噬作为一种真核生物细胞为应对外界刺激而做出的反应, 与固有性和适应性免疫系统有关。一方面, 在NLRP3炎性小体激活过程中会促进自噬; 另一方面, 自噬的过度激活可以抑制NLRP3炎症小体的激活^[84]。

研究表明, hucMSC来源的外泌体能够通过增加自噬相关蛋白LC3-II和beclin1的表达, 抑制脊髓背角NLRP3炎症小体的激活, 从而减轻神经炎症。体外实验证明, hucMSC来源的外泌体预处理的BV2细胞中, NLRP3炎症小体复合物(NLRP3、caspase-1-p20、ASC) 和GSDMD (GSDMD-F、GSDMD-N) 受到抑制。这中间涉及miR-146a-5p/肿瘤坏死因子受体相关因子6 (tumor necrosis factor receptor-associated factor 6, TRAF6) 这一调控轴^[85]。此外, 研究证明人脂肪干细胞来源的外泌体miR-155-5p可以通过调控转化生长因子β受体2 (transforming growth factor beta receptor 2, TGFβR2) 来促进自噬和抑制NLRP3炎症小体的激活, 从而减缓椎间盘退变的发展^[86]。

2.3 间充质干细胞来源的外泌体抑制促炎因子的分泌

体内研究结果表明, hucMSC来源的外泌体通过miR-1208靶向结合METTL3, 降低NLRP3 mRNA的m6A修饰水平, 从而抑制促炎因子的分泌和软骨细胞外基质的降解, 从而缓解小鼠骨关节炎的进展, 为临床骨关节炎的治疗提供了一种新的方法^[87]。体外研究结果证明, 提取过表达miR-100-5p的hucMSC的外泌体后给予AC16细胞, 发现能够阻断AC16细胞缺氧/复氧损伤引起的乳酸脱氢酶释放、细胞焦亡、NLRP3和激活的caspase-1 (p20) 和GSDMD-N的过表达, 以及IL-1β和IL-18的释放^[88]。

2.4 间充质干细胞来源外泌体促进巨噬细胞向抗炎表型转化

根据巨噬细胞的活化状态和功能, 它们可以分为M1型(经典活化巨噬细胞) 和M2型(替代活化巨噬细胞)^[89]。M1巨噬细胞的作用是分泌促炎细胞因子和趋化因子, 呈递抗原, 从而参与免疫应答。M2巨噬细胞主要分泌精氨酸酶I (arginase-I)、IL-10和TGF-β等抗炎细胞因子^{[90, 91]}, 具有减少炎症和促进肿瘤生长及免疫抑制功能^[92]。在特定的微环境中, M1和M2巨噬细胞可以相互转化^[93]。

研究表明, LPS预处理的BMSC-Exos能够将促炎性巨噬细胞转变为促进再生的巨噬细胞。这一转变是通过肿瘤坏死因子(TNF) 刺激基因-6 (TNF stimulated gene-6, TSG-6) 介导的, TSG-6在这些外泌体中的高度富集是实现其功能的关键因素。TSG-6通过抑制NF-κB和NLRP3信号通路, 从而抑制炎症反应并促进巨噬细胞向M2型极化, 这种极化有助于促进神经再生, 为周围神经修复提供了潜在的治疗途径^[94]。

3 免疫细胞来源的外泌体影响NLRP3炎症小体的激活

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免疫细胞是指参与免疫应答或与免疫应答相关的细胞, 在人体的生理和病理过程中担任着重要的角色。免疫细胞可分为先天免疫细胞和适应性免疫细胞两大类, 前者包括巨噬细胞、树突状细胞(dendritic cells, DCs)、NK细胞和中性粒细胞等, 后者主要是T细胞和B细胞。由于免疫细胞的功能存在着差异, 不同的免疫细胞来源的外泌体对NLRP3炎症小体的作用也不尽相同。

3.1 树突状细胞来源的外泌体下调NLRP3炎症小体表达

在人类肝样本中, 急性肝移植排斥组的肝内CD8⁺ T细胞浸润增加, 这一效应伴随着NLRP3和Ki-67指数的高表达以及DCs数量的减少。此外, 在肝移植小鼠模型中观察到急性排斥时CD80⁺ DCs水平较低。研究证明, 来源于CD80⁺ DCs的外泌体通过下调NLRP3表达负向调节CD8⁺ T细胞, 这一系列事件对于减轻急性肝移植排斥至关重要^[95]。

3.2 巨噬细胞来源的外泌体调控NLRP3炎症小体

不同细胞来源的外泌体内容物存在显著差异, 这些差异不仅体现在蛋白质和核酸的种类上, 还体现在其功能和生物学效应上。M1和M2巨噬细胞来源的外泌体对肾上皮细胞的凋亡表现出相反的作用, M1巨噬细胞来源的外泌体表现出促炎作用, 而M2巨噬细胞来源的外泌体表现出抗炎作用。

研究证实, 外泌体miR-93-5p是M1和M2巨噬细胞在炎症状态下对肾上皮细胞的凋亡表现出相反作用的原因。miR-93-5p在M2型巨噬细胞来源的外泌体中的表达明显上调。外泌体miR-93-5p通过直接靶向TXNIP, 抑制NLRP3炎症小体的激活, 从而抑制上皮细胞焦亡通路^[96]。此外, 也有研究表明, M2巨噬细胞来源的外泌体携带的miR-148a可通过下调TXNIP, 抑制TLR4/NF-κB/NLRP3炎症小体信号通路, 减轻心肌缺血再灌注损伤^[59]。该研究为心肌缺血再灌注损伤的治疗提供了新的思路。

4 肿瘤细胞衍生的外泌体通过NLRP3炎症小体调控肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs) 的极化

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肿瘤微环境(tumor microenvironment, TME) 是一个由恶性肿瘤细胞、肿瘤浸润免疫细胞、内皮细胞、基质细胞、肿瘤相关成纤维细胞以及这些细胞分泌的因子如细胞因子和趋化因子共同组成的独特体系^[97]。先前的研究主要集中在肿瘤细胞和免疫细胞之间通过直接接触和分泌信号分子进行细胞传递^[98]。外泌体的发现和研究为肿瘤免疫提供了新的理论基础和实践应用前景。越来越多的证据表明, 外泌体作为一种新型细胞间通信机制, 参与了恶性肿瘤细胞通过TAMs在TME中进行调节。肿瘤源性外泌体可以导致TAMs的极化, 从而增加向TME分泌IL-1β^[99-101]。M1样TAMs具有形成促血管生成和促炎状态的趋势, 而M2样TAM倾向于参与组织重塑^[102]。肿瘤源性外泌体(tumor-derived exosomes, TDEs) 参与不同肿瘤过程的形成和发展, 包括TME重构、血管生成、侵袭、转移和耐药等。

TAMs的代谢重编程与癌症的发展相关。有研究报道了TDEs的TRIM59 (tripartite motif containing 59) 通过调节α/β水解酶结构域5 (abhydrolase domain containing 5, ABHD5) 蛋白酶体降解, 将巨噬细胞转化为具有促瘤功能的巨噬细胞, 激活NLRP3炎性小体信号通路, 通过分泌IL-1β促进肺癌进展^[103]。TRIM59直接诱导ABHD5泛素化, 导致其蛋白酶体依赖性降解。ABHD5是脂质代谢的重要调节因子, 其缺乏已被证明是巨噬细胞重编程和NF-κB依赖性NLRP3炎症小体通路激活的许可信号^[104]。基于此, 外泌体有望成为多种癌症的潜在治疗靶点, 但需要进一步的研究来验证外泌体介导的NLRP3炎性小体活性在癌症进展中的精确机制。

5 其他来源的外泌体对NLRP3炎症小体激活的作用

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除了上述细胞来源的外泌体在NLRP3炎症小体的调控中能够起到一定的作用外, 还有一些其他来源的外泌体能够调控NLRP3炎症小体(表 1^{[59, 105-108]})。人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs) 来源的外泌体能通过DDX3X/NLRP3通路促进巨噬细胞M2极化, 减少NLRP3表达, 有利于血管生成和骨再生。相反, 在急性心肌梗死情况下, 心脏微血管内皮细胞(cardiac microvascular endothelial cells, CMECs) 因氧化应激产生的自噬体无法正常降解, 导致腺上皮细胞1 (glandular epithelial cells 1, GEC1) 自噬体经由外泌体释放, 增加NLRP3炎症小体水平, 加剧血管炎症。此外, 研究还揭示了足细胞在高同型半胱氨酸血症中通过ROS介导的外泌体分泌促进NLRP3炎症小体激活, 进而引发肾小球炎症。

不仅仅是细胞来源的外泌体可以调控NLRP3炎症小体(图 1), 一些体液来源的外泌体也可以调控NLRP3炎症小体。唾液外泌体中的miR-223-3p能下调NLRP3表达, 减轻牙周炎中的细胞焦亡; 以及重症2019新型冠状病毒(coronavirus disease 2019, COVID-19) 患者的血浆外泌体可在远端器官触发NLRP3炎症小体, 引起炎症反应。这些发现为理解外泌体在疾病进展中的作用提供了新的视角(表 1)。

6 外泌体在NLRP3炎症小体相关疾病的治疗潜力

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外泌体具有低免疫原性、高稳定性、易于储存和管理等优点, 与细胞疗法等相比, 外泌体疗法展现出更大的优势和潜力。MSC由于其强大的免疫调节和再生特性而广泛用于细胞治疗。研究已经证明, 与MSC本身相比, MSC-Exos在有效减少不良反应(如输注相关的毒性) 方面具有显著优势^[109]。MSC-Exos正在成为一种有前途的无细胞治疗工具, 越来越多的临床研究开始评估MSC-Exos在不同疾病中的治疗效果。

6.1 神经退行性疾病

外泌体通过调节NLRP3炎症小体的激活, 在多种疾病中展现出显著的治疗潜力。特别是在神经退行性疾病如帕金森病(Parkinson's disease, PD) 中, 外泌体疗法已经显示出一定的疗效。研究表明, 利用富含miR-188-3p的外泌体处理1-甲基-4-苯基-1, 2, 4, 5-四氢吡啶(MPTP) 诱导的帕金森病小鼠模型和神经毒素1-甲基-4-苯基吡啶(MPP⁺) 诱导的细胞模型, 评估其损伤、自噬和炎症小体的水平。在小鼠和MN9D细胞中, miR-188-3p富集的脂肪干细胞源性外泌体通过靶向细胞周期蛋白依赖性激酶5 (cyclin-dependent kinase 5, CDK5) 和NLRP3抑制自噬和焦亡, 并促进增殖。miR-188-3p有望成为PD患者新的治疗靶点^[110]。

6.2 心血管系统疾病

外泌体在心血管系统疾病的治疗上也具有潜力。有研究显示, 人参皂苷Rh2通过高迁移率族蛋白B1 (high mobility group box 1, HMGB1)/NF-κB信号通路抑制NLRP3炎症小体活化, 促进外泌体治疗心肌损伤。Rh2可以通过增强外泌体对心肌损伤的保护来改善炎症微环境, 为Rh2间接修饰外泌体在心肌梗死治疗中的作用提供了新的见解^[111]。

6.3 癌症治疗

在癌症治疗中, 可以通过外泌体miR-21的递送来抑制TAMs的NLRP3炎症小体活性, 以增强化疗效果。机制上, miR-21通过抑制磷酸酯酶与张力蛋白同源物(phosphatase and tensin homolog, PTEN) 和含BRCA1/BRCA2复合体3 (BRCA1-BRCA2-containing complex 3, BRCC3) 促进NLRP3磷酸化和赖氨酸-63泛素化, 从而抑制NLRP3炎症小体的组装^[112]。

外泌体在NLRP3炎症小体相关疾病的治疗中展现出显著的潜力, 主要通过调节和抑制NLRP3炎症小体的激活来发挥作用。外泌体通过多种方式调节和抑制NLRP3炎症小体的激活, 包括直接抑制相关通路的激活、降低炎症因子的表达以及通过miRNA介导的调控等。这些机制共同作用, 使外泌体成为治疗NLRP3炎症小体相关疾病的重要工具。

7 总结与展望

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外泌体自1983年被发现至今已有40多年的历史。在这期间, 与外泌体相关的研究取得了显著进展。外泌体在生理和病理状态下都扮演着至关重要的角色^[113], 不仅在细胞间通讯和免疫调节中起着关键作用, 还在疾病的诊断和治疗中展现出巨大的潜力。进一步的研究加深了研究者对于疾病中外泌体与炎症之间相互作用的理解, 特别强调了外泌体对调控NLRP3炎症小体的重要性。

近年来的研究显示, 外泌体能够调节NLRP3炎症小体, 进而影响疾病的进程。如外泌体中的miR-148a通过TXNIP-NLRP3-caspase-1信号通路减少了缺血性心肌的损伤^[114]。HMGB1能够与Toll样受体结合并激活NLRP3途径, 研究发现来自MSC-Exos的miR-126能够通过下调HMGB1的表达来抑制高血糖引起的炎症反应^[115]。深入探索外泌体调控NLRP3的分子机制将有助于推动其在临床治疗中的应用。然而, 当前对于外泌体在疾病中具体作用机制的研究仍存在局限性。多数研究通过“功能获得性”实验来验证其分子机制, 这可能在一定程度上限制了研究者对外泌体全面功能的认识。外泌体如何与靶细胞相互作用、如何调节细胞内信号通路等关键问题仍需进一步深入研究。此外, 非经典炎症小体在多种炎症性疾病中扮演着关键角色, 如脓毒症、自身免疫疾病和肿瘤相关炎症等。外泌体对NLRP3炎症小体以外的其他炎症小体的调控作用及机制的研究相对较少。未来的研究应进一步探索外泌体对其他炎症小体的具体调控机制, 并优化其临床应用策略, 以期为炎症相关疾病的治疗带来新的希望。

目前, 针对NLRP3炎症小体相关疾病的防治策略主要包括研发NLRP3炎症小体抑制剂, 包括小分子化合物(如MCC950、OLT1177)、天然产物(如β-羟基丁酸、ω-3脂肪酸)、临床药物等, 这些抑制剂能够直接靶向NLRP3炎症小体, 抑制其激活, 从而发挥抗炎作用; 或者开发能够抑制相关信号通路(如mTOR、磷酸化、TRPC1降解等) 的药物来调控NLRP3炎症小体的激活, 从而达到抗炎效果; 以及通过使用中和抗体和IL-1β受体拮抗剂来抑制IL-1β的活性, 从而减轻炎症反应。然而, 这些方法存在不良反应等弊端。

关于外泌体对NLRP3炎症小体的调控可能存在的互作模式, 外泌体通过携带和传递各种分子(如miRNA、蛋白质等), 能够抑制或激活NLRP3炎症小体的途径, 从而在疾病进展中发挥双重调控作用。外泌体的这些作用为开发新的治疗策略提供了可能。通过调控外泌体的分泌或功能, 可能抑制NLRP3炎症小体的激活, 从而减轻疾病症状。如靶向外泌体中的特定分子或改变其生物分布, 可能有助于治疗与NLRP3炎症小体激活相关的疾病。

鉴于外泌体在疾病治疗中的巨大潜力, 未来研究应致力于打破现有瓶颈, 通过更深入的分子机制研究和创新的实验设计, 为临床治疗带来突破性进展。期待研究者有更多高质量的研究能够突破瓶颈, 为外泌体在医学领域的应用开辟新的道路。

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doi: 10.16438/j.0513-4870.2024-0909

接收时间：2024-09-18
首发时间：2025-10-29
出版时间：2025-04-12

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收稿日期：2024-09-18
修回日期：2024-12-26

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国家自然科学基金资助项目(82373870)

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中国药科大学基础医学与临床药学学院, 江苏南京 210009

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徐明, Tel: 15805195696, E-mail: mingxu2016@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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