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. 2023 Jun 20;43(6):994–1001. [Article in Chinese] doi: 10.12122/j.issn.1673-4254.2023.06.15

脂多糖刺激巨噬细胞分泌含miR-155-5p的外泌体促进肝星状细胞的活化及迁移

Lipopolysaccharide stimulates macrophages to secrete exosomes containing miR-155-5p to promote activation and migration of hepatic stellate cells

Jiayi LIN 1, Anni LOU 1, Xu LI 1,2,*
PMCID: PMC10339300  PMID: 37439172

Abstract

Objective

To observe the effect of exosomes secreted by lipopolysaccharides (LPS)-stimulated macrophages on hepatic stellate cell activation and migration and explore the underlying molecular mechanism.

Methods

Human monocyte THP-1 cells were induced to differentiate into macrophages using propylene glycol methyl ether acetic acid (PMA, 100 ng/mL, 24 h) followed by stimulation with LPS, and the culture supernatant of macrophages was collected for extraction of the exosomes by ultracentrifugation. The expression of miR-155-5p in the exosomes was detected using qRT-PCR. A Transwell co-culture system was used to observe the effects of the macrophage-derived exosomes on LX2 cell (a hepatic stellate cell line) proliferation, migration, oxidative stress and the expression of fibrosis biomarkers, which were also observed in LX2 cells transfected with miR-155-5p-mimics or miR-155-5p-inhibitors. Western blotting was used to detect the expressions of SOCS1 and its downstream signal pathway proteins.

Results

Treatment with the exosomes from LPS-stimulated macrophages significantly enhanced the proliferation and migration ability of LX2 cells and increased the levels of oxidative stress and expressions of the fibrosis markers such as type Ⅰ collagen (P < 0.05). The expression of miR-155-5p in the exosomes secreted by macrophages was significantly increased after LPS treatment (P < 0.01). LX2 cells overexpressing miR-155-5p also exhibited significantly enhanced proliferation and migration with increased oxidative stress levels and expression of type Ⅰ collagen (P < 0.05), and interference of miR-155-5p expression produced the opposite effects. Western blotting showed that miR-155-5p overexpression obviously inhibited SOCS1 expression and promoted p-Smad2/3, Smad2/3 and RhoA protein expressions in LX2 cells (P < 0.05).

Conclusion

LPS stimulation of the macrophages increases miR-155-5p expression in the exosomes to promote activation and migration and increase oxidative stress and collagen production in hepatic stellate cells.

Keywords: lipopolysaccharide, macrophage, exosome, microRNA-155-5p, hepatic stellate cells, liver fibrosis

肝纤维化是肝炎-肝硬化-肝癌三部曲的重要病理表型，研究表明抑制肝纤维化能有效减缓肝炎向肝癌的进程[1]。但目前临床上针对肝纤维化没有行之有效的治疗方案[2]。因而，深入探索纤维化机制为寻找延缓乃至逆转纤维化的治疗靶点和节约医疗资源具有十分重要意义。

肝巨噬细胞在肝纤维化中发挥至关重要的作用，其主要功能与炎症、肝细胞损伤、肝星状细胞的活化和纤维化密切相关[3]。肝星状细胞在肝脏生理和纤维生成起到关键作用，其能够受到肝巨噬细胞的调控[4]。近来研究表明，巨噬细胞可以分泌外泌体影响组织周围的细胞，促进细胞表型转化，增强迁移能力等，这提示肝脏巨噬细胞可能对肝纤维化起着重要作用[5, 6]。而外泌体可携带microRNA(miRNA)，能够对靶细胞的mRNA进行编辑。外泌体miRNA失调与肝损伤、肝纤维化和肝癌的发生有关，是评估和治疗肝病的一种有前途的治疗策略[7]。文献报道显示miR-155-5p与肝纤维化调控密切相关[8, 9]。然而肝巨噬细胞外泌体中是否富集miR-155-5p且参与调控肝星状细胞的活化和纤维化还不清楚。SOCS1是miR-155-5p调控的靶基因之一，且SOCS1可抑制肝脏的纤维化[10]。SOCS1的过表达沉默TGF-β 1/Smad2/3信号通路，改通路和纤维化密切相关[11]。

因此，本项目研究已活化巨噬细胞分泌的外泌体能否刺激肝星状细胞增殖活化和迁移，诱导肝纤维化的作用，并通过外泌体miR-155-5p研究巨噬细胞外泌体能否通过SOCS1刺激肝星状细胞纤维化的机制，明确外泌体miR-155-5p在肝巨噬细胞对肝星状细胞的纤维化机制中的作用，为肝纤维化的治疗提供靶点。

1. 材料和方法

1.1. 材料

人单核细胞系THP-1(ATCC)，肝星状细胞LX2(中科院)；脂多糖(LPS，L2880)、PKH26红色荧光细胞标记试剂盒、佛波酯PMA(P1585)(sigma)；miR-155-3p、miR-155-5p和U6引物(锐博)；CCK-8试剂盒(Medchemexpress)、脂质氧化(MDA)检测试剂盒和兔IgG(碧云天)；Lipofectamine® 3000试剂(Thermo)。Anti-GAPDH抗体、Collagen Type Ⅰ Monoclonal Antibody抗体、CD63 Polyclonal Antibody抗体和CD9 Polyclonal Antibody抗体(Proteintech)；TGFB1 Rabbit pAb抗体和TSG101/VPS23 Rabbit mAb抗体(ABclonal)；Anti-α-SMA抗体(Boster)；SOCS1(E4K7Q)Rabbit mAb抗体(CST)；Anti-Smad2+Smad3抗体、Anti-Smad2 + Smad3抗体和Anti-RhoA抗体(Abcam)。

1.2. 方法

1.2.1. 细胞培养、外泌体提取和鉴定

人肝星状细胞LX2用完全培养基(90%的DMEM+10%FBS)培养，人单核细胞系THP-1所用完全培养基为90%1640+10% FBS+0.05MM巯基乙醇。THP-1用PMA(100 ng/mL，24 h)避光诱导分化为巨噬细胞。收集用脂多糖(1 μg/mL，24 h)刺激的巨噬细胞上清，用超速离心法提取外泌体。提取后的外泌体做NTA鉴定和透射电子显微镜成像确定外泌体的大小和形态特征。并用BCA蛋白浓度测定法测其蛋白浓度，可于-80 ℃下保存。Western blot测定3个外泌体标记蛋白TSG101、CD63和CD9。用PKH26荧光标记上层巨噬细胞外泌体，和LX2细胞避光共培养24 h后用激光共聚焦显微镜成像。

1.2.2. 划痕

根据实验要求用细胞培养板六孔板种植LX2细胞。六孔板事先用marker笔照着直尺均匀划线，大约每隔0.5~1 cm一道，横穿整个孔，每孔至少划5条线。用100 μL枪头垂直地面，照着画线划痕，用PBS洗3遍，换上无血清培养基，放入37 ℃，5%CO2培养箱中培养。在光学显微镜下观察拍照。

1.2.3. 蛋白质印迹试验

提取细胞的总蛋白质，检测蛋白质浓度，SDS-PAGE凝胶电泳分离蛋白，然后进行电转，然后依次进敷一抗、清洗、敷二抗、清洗、然后干燥、扫描和拍照。

1.2.4. CCK8检测

本课题采用CCK-8试剂盒来检测细胞的增殖情况，操作按照使用说明书。

1.2.5. 脂质氧化丙二醛(MDA)检测

MDA采用了碧云天的脂质氧化检测试剂盒进行检测，操作步骤见使用说明书。

1.2.6. EdU细胞增殖检测实验

培养LX2细胞，处理后标记EdU到细胞上，然后固定细胞进行细胞核DAPI染色染色完成后在BX63全自动智能荧光显微镜下检测。

1.2.7. 细胞转染

将培养状态良好的LX2细胞铺在六孔板中，保持有30%~40%的细胞密度。先用Opti-MEM培养基稀释Lipofectamine® 3000试剂(2管)，充分混匀。再用Opti-MEM培养基稀释miR-155-5p-mimics、miR-155-5p-mimics-NC、miR-155-5p-inhibitors和miR-155-5p-inhibitors-NC(各2管)。充分混匀。混合对应的A和B管，室温孵育10~15 min，加入到事先铺好细胞的六孔板中，在37 ℃，5% CO2恒温敷箱中孵育72 h。1.2.8 qRT-PCR检测步骤参考以往文献[12]。引物序列如下：SOCS1上游引物：5'-CCAGGTGGCAGCCG ACAATG-3'；下游引物：5'-CGAGGAGGAGGAAGA GGAGGAAG-3'；aSMA上游引物：5'-AAAGCAAGT CCTCCAGCGTT-3'；下游引物：5'-TAGTCCCGGGGA TAGGCAAA-3'；Col1A1上游引物：5'-CCCGGGTTTC AGAGACAACTTC-3'；下游引物：5'-TCCACATGCTT TATTCCAGCAATC-3'；TGF-B1上游引物：5'-ACATC AACGCAGGGTTCACT-3'；下游引物：5'-AGAAGTT GGCATGGTAGCCC-3'。

1.3. 统计学分析

所有的实验数据经过科学检测分析，使用SPSS 19.0软件进行统计学分析。所有数据经正态性检验。数据以均数±标准差表示，采用两独立样本t检验，P < 0.05时认为差异具有统计学意义。

2. 结果

2.1. 巨噬细胞来源外泌体能够被肝星状细胞摄取

通过显微镜和流式细胞实验验证了PMA成功诱导THP-1为巨噬细胞(图 1A、B)。脂多糖(1 μg/mL，24 h) 刺激(LPS-Exo)和正常培养(CTR-Exo)后收集的外泌体呈现双层膜盘状囊泡的外形，形状为椭圆形或不规则圆形，均一性良好，大小基本分布在90~150 nm (图 1C)。CTR-Exo的粒径峰值为106 nm，LPS-Exo的粒径峰值为125 nm(图 1D)，分布在90~150 nm。收集的外泌体均表达外泌体的标志物蛋白TSG101、CD63、CD9(图 1E)。PKH26红色荧光标记的外泌体与DAPI标记的蓝色荧光在LX2细胞中共定位，并且随着时间的推移红色荧光量明显增多(图 1F)。

图 1.

图 1

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外泌体的鉴定和转移追踪

Identification and transfer tracking of exosomes from the macrophages. A, B: PMA induction of THP-1 cells into macrophages observed by microscopy and flow cytometry. C: Transmission electron microscopy of the exosomes (Scale bar: 200 nm). D: Results of nanoparticle tracking analysis (NTA) of the exosomes. E: Expressions of the protein markers TSG101, CD63 and CD9 in the exosomes analyzed by Western blotting. F: Colocalization of the exosomes and LX2 cells. The exosome membrane is labeled with PKH26 (red fluorescence) and LX2 cell nuclei with DAPI (blue).

2.2. 脂多糖刺激的巨噬细胞分泌的外泌体促进LX2的增殖、迁移、氧化应激和纤维化

脂多糖处理的巨噬细胞的外泌体处理的LX2 (LPS-LX2组)红色荧光比正常培养的巨噬细胞的外泌体处理的LX2(CTR-LX2组)明显增多(图 2A)；LPSLX2组LX2细胞的增殖显著高于CTR-LX2组(P < 0.01，图 2B)。LPS-LX2组LX2细胞的氧化应激标志物MDA水平显著高于CTR-LX2组水平(P < 0.001，图 2C)。LPS-LX2组的LX2细胞向空白区域的迁移能力显著高于CTR-LX2组(图 2D)。LX2细胞活化和纤维化的标志物是α-SMA，TGF-β和Col1A1，LPS-LX2组活化和纤维化标志物的mRNA和蛋白水平都明显高于CTRLX2组(P < 0.001，图 2E、F)。

图 2.

图 2

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LPS-Exo促进LX2的增殖、氧化应激水平、迁移及纤维化表型的表达

LPS-Exo treatment increases proliferation, oxidative stress level, migration efficiency, and fibrotic phenotype of LX2 cells. A: Edu cell proliferation assay showing the effect of LPS-Exo on proliferation of LX2 cells after exosome co-culture. B: CCK-8 assay for analyzing the effect of LPS-Exo on proliferation of LX2 cells after exosome co-culture. C: Lipid oxidation (MDA) assay showing the effect of LPS-Exo on MDA level in LX2 cells after exosome co-culture. D: Scratch assay for analyzing the effect of LPS-Exo on migration of LX2 cells after exosome co-culture. E: qRT-PCR for detecting mRNA expressions of α-SMA, TGF-β, and Col1a1 in LX2 cells after exosome co-culture. F: Western blotting for detecting protein expression of α-SMA, TGF-β, and Col1a1 in LX2 cells after exosome co-culture. Data are presented as Mean±SD from 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 vs CTR-LX2 group.

2.3. 脂多糖诱导巨噬细胞外泌体miR-155-5p对LX2细胞功能的影响

随着脂多糖刺激浓度增加，巨噬细胞外泌体中miR-155-5p的表达水平显著上升(P < 0.01，图 3A)。miR-155-5p表达在miR-155-5p mimics组中显著增加，而在miR-155-5p inhibitors组中显著降低(P < 0.001，图 3B)。和对照组(miR-155-5p mimics-NC)相比，miR-155-5p mimics组增殖、氧化应激标志物MDA水平以及纤维化标志物α-SMA、TGF-β和Col1a1 mRNA和蛋白水平显著增加，而miR-155-5p inhibitor组发挥相反的作用(图 3C~G)。巨噬细胞外泌体的miR-155-5p促进了LX2细胞迁移(图 3H)。

图 3.

图 3

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miR-155-5p对LX2细胞增殖、迁移、氧化应激和纤维化的影响

Effects of miR-155-5p on proliferation, migration, oxidative stress and fibrosis of LX2 cells. A: Effect of LPS treatment on miR-155-5p expression assessed by qRT-PCR. B: qRT-PCR for detecting miR-155-5p expression in LX2 cells treated with miR-155-5p mimics and inhibitors. C: CCK8 assay showing the effect of miR-155-5p on proliferation of LX2 cells after transfection. D: Lipid oxidation (MDA) assay showed the levels of oxidative stress in the cells after transfection. E: Edu cell proliferation assay showing the effect of miR-155-5p on the proliferation of LX2 cells. F: qRT-PCR for detecting mRNA expressions of α-SMA, TGF-β, and Col1a1 in LX2 cells after transfection. G: Western blotting for detecting protein expressions of α-SMA, TGF-β, and Col1a1 in LX2 cells after transfection. H: Scratch test showing the effect of miR-155-5p on the migration of LX2 cells after transfection. Data are presented as Mean±SD from 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 vs control group.

2.4. 巨噬细胞外泌体miR-155-5p对肝星状细胞SOCS1及促纤维化因子的影响

和CTR-LX2相比，LPS-LX2组SOCS1 mRNA和蛋白显著降低(图 4A、C)。和对照组(miR-155-5pmimicsNC)相比，miR-155-5p mimics组SOCS1 mRNA和蛋白显著降低，而miR-155-5p inhibitor组SOCS1 mRNA和蛋白显著升高(图 4B、D)。而TGF-β1/Smad通路中的关键蛋白p-Smad2/3、samd2/3以及RhoA/ROCK1通路中的关键蛋白RhoA蛋白的表达趋势和SOCS1相反(图 4B、D)。

图 4.

图 4

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miR-155-5p对肝星状细胞SOCS1表达及促纤维化信号通路的影响

Effects of miR-155-5p on expression of SOCS1 and fibrosis signal axis-related proteins in LX2 cells. A: SOCS1 mRNAs in LX2 cells analyzed by qRT-PCR after treatment with LPS. B: SOCS1 mRNAs in LX2 cells treated with miR-155 inhibitor or miR-155 mimic analyzed by qRT-PCR. C: Protein expressions of SOCS1, p-Smad2/3, samd2/3, and RhoA in LX2 cells treated with miR-155 mimics or miR-155 inhibitor analyzed by Western blotting. D: Protein expressions of SOCS1, p-Smad2/3, samd2/3, and RhoA in LX2 cells treated with miR-155 mimic or miR-155 inhibitor analyzed by Western blotting. Data are presented as Mean ± SD from 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 vs control group.

3. 讨论

巨噬细胞是肝脏重要的天然免疫细胞，对肝脏损伤、炎症和纤维化有重要的调控作用。肝星状细胞的活化是肝纤维化的重要始动环节，巨噬细胞的旁分泌对肝星状细胞的活化发挥重要的调控作用，然而目前机制仍然完全不明确[3]。因此，研究巨噬细胞和肝星状细胞之间的联系，对于有效阻断肝星状细胞的活化有积极的意义。外泌体介导的纤维化调控也是近年来器官纤维化研究的方向[5]。以往研究表明巨噬细胞和肝星状细胞之间能够通过外泌体进行调控[13, 14]，但机制仍不完全明确，值得进一步探讨。本文研究发现脂多糖诱导的巨噬细胞外泌体能够促进LX2细胞的增殖活化，提高其氧化应激反应水平，合成纤维化进程所需蛋白，从而进一步诱导肝纤维化。

miRNA通过与特定的mRNA靶标结合并促进其降解和/或翻译抑制其转录后表达。miRNA能够调节肝脏的生理功能和病理功能[15]。miRNA的表达改变与肝脏代谢失调、肝脏损伤、肝纤维化和肝癌发展有关，这使miRNA成为诊断和治疗肝病的有吸引力的治疗策略。有研究表明脂多糖激活的巨噬细胞的外体miR-103-3p和miR-500有助于肝星状细胞的活化[16, 17]。M1巨噬细胞极化通过巨噬细胞外体miR-125b-5p调控Stard13蛋白表达的来增强肝星状细胞活化[18]。M2巨噬细胞衍生的外泌体miR-411-5p通过靶向CAMSAP1来阻止肝星状细胞的活化[19]。以上研究表明脂多糖刺激的巨噬细胞(M1型)能够通过转移miRNA促进肝星状细胞活化，而M2型巨噬细胞能够通过转移miRNA抑制肝星状细胞活化。在本研究中发现脂多糖诱导肝巨噬细胞外泌体miR-155-5p含量明显增多，而miR-155-5p促进肝星状细胞的活化、迁移、氧化应激及胶原生成，表明脂多糖激活的巨噬细胞的外体miR-155-5p有助于肝星状细胞的活化。

SOCS1是miR-155-5p调控的潜在靶基因。有研究报道SOCS1可抑制肝脏纤维化[20, 21]。RhoA/ROCK1通路和TGF-β1/Smad2/3通路的激活也和肝纤维化密切相关[22, 23]。而SOCS1能够抑制RhoA/ROCK1通路和TGF-β1/Smad2/3通路的激活[24, 25]。本文研究表明脂多糖刺激巨噬细胞后其外泌体可抑制肝星状细胞SOCS1的表达，此外，肝星状细胞miR-155-5p上调或抑制后，SOCS1相应出现同反的趋势，表明了SOCS1是miR-155-5p发挥其作用的潜在靶点。本文还发现miR-155-5p可以激活RhoA/ROCK1通路和TGF-β1/Smad2/3通路。

相关研究报道了miR-155-5p在不同的脏器的纤维化中具有不同作用[26-28]。有研究报道miR-155-5p通过SOCS1促进了肾脏纤维化，然而研究发现miR-155-5p靶向JADE-1和NR3C2促进了肾癌细胞的增殖、迁移和侵袭[29, 30]。巨噬细胞来源的M2外泌体中的miR-155-5p促进了结肠癌细胞迁移和侵袭[31]。通过抑制miR-155-5p调节Meprin α在硅小鼠中发挥抗肺纤维化作用[32]。因此miR-155-5p通过不同的分子机制在各脏器中发挥作用。由于miR-155-5p以及其下游基因在不同脏器的表达具有差异性，因此miR-155-5p在不同的脏器中展现的功能需要进一步研究进行验证。然而，我们发现miR-155-5p促进了肝细胞纤维化，其机制有MiR-155-5p-SOCS1/JAK1/STAT1通过调节M1巨噬细胞极化参与肝纤维化和肝硬化的肝淋巴管生成[9]，miR-155-5p在丙肝患者中表达显著上调，在丙肝感染患者的肝细胞癌伴肝硬化中的具有诊断意义[33]，此外，miR-155-5p通过PI3K/Akt促进了肝癌细胞增殖[34]。由于miRNA主要通过调控其下游基因翻译过程而发挥生物学功能，miR-155-5p以及其下游基因在不同脏器的表达具有差异性，因此miR-155-5p在不同的脏器中展现不一样的功能。由此可见，miR-155-5p主要对肝细胞起到了活化的作用。本次研究也揭示了miR-155-5p通过靶向抑制SOCS1激活RhoA/ROCK1通路和TGF-β1/Smad2/3通路的分子机制，但是还需要对SOCS1进行补救实验加以证明。

本研究还存在以下几点不足。首先仅在细胞层面观察了外泌体miR-155-5p介导的巨噬细胞和肝星状细胞之间的相互作用，没有在动物实验层面研究。miR-155-5p在肝纤维化患者中的表达以及和临床相指标的相关性还有待进一步分析。最后缺少巨噬细胞干预miR-155-5p的表达，直接证明其对肝星状细胞的调控作用。

综上，本研究表明巨噬细胞受脂多糖刺激后，分泌含有miR-155-5p的外泌体，miR-155-5p促进肝星状细胞的活化、迁移、氧化应激及胶原生成，机制和SOCS1/RhoA/ROCK1通路和TGF-β1/Smad2/3通路有关。本研究对于阻断内毒素对肝星状细胞的激活效应以及对肝损伤后纤维化的作用和机制有积极的意义。

Biography

林嘉宜，在读硕士研究生，E-mail: linjy9510@163.com

Funding Statement

广州市科技计划项目(201904010482)；广东省自然科学基金(2021A1515012595，2017B020209003)；急救与创伤研究教育部重点实验室(海南医学院)开放课题基金(Grant. KLET-202102)

Contributor Information

林 嘉宜 (Jiayi LIN), Email: linjy9510@163.com.

李 旭 (Xu LI), Email: mylx99@163.com.

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