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Mutual regulation of microglia and astrocytes after Gas6 inhibits spinal cord injury

Neural Regeneration Research 2025年第2期20卷 557-573页

作者： Jiewen Chen Xiaolin Zeng Le Wang Wenwu Zhang Gang Li Xing Cheng Peiqiang Su Yong Wan Xiang Li Department of Spine Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong ProvinceChina Guangdong Province Key Laboratory of Orthopedics and Traumatology GuangzhouGuangdong ProvinceChina

Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury.Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction.However,the mechanisms involved remain unclear.In this study,we found that after spinal cord injury,resting microglia(M0)were polarized into pro-inflammatory phenotypes(MG1 and MG3),while resting astrocytes were polarized into reactive and scar-forming phenotypes.The expression of growth arrest-specific 6(Gas6)and its receptor axl were significantly down-regulated in microglia and astrocytes after spinal cord injury.In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia,and even inhibited the cross-regulation between them.We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway.This,in turn,inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways.In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord,thereby promoting tissue repair and motor function recovery.Overall,Gas6 may play a role in the treatment of spinal cord injury.It can inhibit the inflammatory pathway of microglia and polarization of astrocytes,attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment,and thereby alleviate local inflammation and reduce scar formation in the spinal cord.

关键词： astrocytes axl cell polarization Gas6 Hippo signal inflammatory micro-environment intercellular interaction microglia single-cell sequencing spinal cord injury

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受体酪氨酸激酶axl在肿瘤生物学中的作用研究进展

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现代肿瘤医学 2024年第1期32卷 167-171页

作者：何凯桐周阳王明珠郭婷孙轶华哈尔滨医科大学附属肿瘤医院检验科黑龙江哈尔滨150086 菏泽医学专科学校免疫学检验教研室山东菏泽274000

axl是一种受体酪氨酸激酶(receptor tyrosine kinase,RTK),属于TAM(TYRO3-axl-MER)家族。在生理条件下,axl表达于人体的心脏、骨骼肌、甲状腺中。axl通过调控多条信号通路介导了肿瘤细胞的血管生成、迁移、侵袭、增殖与转移等过程。此外... 详细信息

axl是一种受体酪氨酸激酶(receptor tyrosine kinase,RTK),属于TAM(TYRO3-axl-MER)家族。在生理条件下,axl表达于人体的心脏、骨骼肌、甲状腺中。axl通过调控多条信号通路介导了肿瘤细胞的血管生成、迁移、侵袭、增殖与转移等过程。此外,axl在多种癌症中高表达,对于肿瘤患者的预后评价具有重要意义,并极有可能成为一种新的诊断及预后生物标志物和治疗靶点。本文就近年来axl在肿瘤生物学中的作用研究进展进行综述。

关键词：受体酪氨酸激酶 axl 肿瘤耐药

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血清Occludin、axl水平与急性缺血性脑卒中溶栓后出血转化的关系

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国际检验医学杂志 2024年第2期45卷 246-249页

作者：张立娜王海虹王适达保定市第二中心医院老年病科河北保定072750 保定市第二中心医院神经内二科河北保定072750 保定市第二中心医院功能科河北保定072750

目的探讨血清闭合蛋白(Occludin)、axl水平与急性缺血性脑卒中(AIS)溶栓治疗后出血转化(HT)的关系。方法选取2019年1月至2022年1月该院AIS患者126例为研究对象,根据是否发生HT分为HT组(43例)和非HT组(83例)。比较两组一般资料及血清Occl... 详细信息

目的探讨血清闭合蛋白(Occludin)、axl水平与急性缺血性脑卒中(AIS)溶栓治疗后出血转化(HT)的关系。方法选取2019年1月至2022年1月该院AIS患者126例为研究对象,根据是否发生HT分为HT组(43例)和非HT组(83例)。比较两组一般资料及血清Occludin、axl水平,采用多因素Logistic回归分析AIS患者发生HT的影响因素,采用受试者工作特征(ROC)曲线分析血清Occludin、axl对AIS患者发生HT的预测价值,并分析血清Occludin、axl预测HT发生的交互作用。结果两组心房颤动、入院时美国国立卫生研究院卒中量表(NIHSS)评分及血清Occludin、axl水平比较,差异有统计学意义(Paxl低水平均为AIS患者发生HT的独立危险因素(Paxl预测AIS患者溶栓治疗后HT风险均有较高价值,二者联合预测的曲线下面积(AUC)、灵敏度、特异度分别为0.742、70.73%、66.93%。Occludin和axl对HT发生存在负向交互作用。结论AIS患者血清Occludin、axl均异常表达,可作为HT的预测指标,且二者对HT发生存在负向交互作用。

关键词：闭合蛋白 axl 急性缺血性脑卒中出血转化交互作用

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The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the axl pathway

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1288-1304页

作者： Geni Ye Maohua Huang Yong Li Jie Ouyang Minfeng Chen Qing Wen Xiaobo Li Huhu Zeng Pei Long Zepei Fan Junqiang Yin Wencai Ye Dongmei Zhang College of Pharmacy Jinan UniversityGuangzhou 510632China Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research Jinan UniversityGuangzhou 510632China Integrated Chinese and Western Medicine Postdoctoral Research Station Jinan UniversityGuangzhou 510632China Department of Musculoskeletal Oncology the First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently,there are no molecular targeted drugs approved for osteosarcoma treatment,particularly effective drugs for osteosarcoma with pulmonary metastases.It has been reported that fibroblast activation protein alpha(FAPa)is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis,demonstrating that FAPa-targeted agents might be a promising therapeutic strategy for osteosarcoma.In the present study,we reported that the FAPa-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPa-positive osteosarcoma cells in vitro and in vivo.Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells.Importantly,it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition(EMT)of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo.Mechanistically,Z-GP-DAVLBH suppressed the axl/AKT/GSK-3β/β-catenin pathway,leading to inhibition of the growth and metastatic spread of osteosarcoma cells.These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPa-positive osteosarcoma,particularly osteosarcoma with pulmonary metastases.

关键词： Osteosarcoma Fibroblast activation protein alpha Growth Pulmonary metastasis Vinblastine prodrug axl β-Catenin

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axl在鼻咽癌中的功能及表达调控的分子机制

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中南大学学报（医学版） 2022年第6期47卷 685-697页

作者：周珂帆赵锦胥洪鹃颜学军刘卫东蒋星军任彩萍中南大学基础医学院肿瘤研究所长沙410078 中南大学湘雅医院神经外科长沙410008

目的:鼻咽癌(nasopharyngeal carcinoma,NPC)是一种高侵袭性的上皮源性恶性肿瘤,具有独特的地理和种族分布特征,多发于中国南方和东南亚地区,其治疗主要依靠放射治疗和化学治疗。但NPC通常发现于晚期,且常出现局部复发和远处转移,患者... 详细信息

目的:鼻咽癌(nasopharyngeal carcinoma,NPC)是一种高侵袭性的上皮源性恶性肿瘤,具有独特的地理和种族分布特征,多发于中国南方和东南亚地区,其治疗主要依靠放射治疗和化学治疗。但NPC通常发现于晚期,且常出现局部复发和远处转移,患者预后较差。受体酪氨酸激酶axl在多种肿瘤中表达上调,参与肿瘤增殖、迁移、侵袭等过程,与肿瘤不良预后相关。本研究旨在检测axl在NPC细胞系及组织中的表达,探讨axl在NPC中的生物学功能及表达调控的分子机制。方法:利用基因表达综合(Gene Expression Omnibus,GEO)数据库中的GSE68799、GSE12452、GSE53819三个数据集分析axl在正常鼻咽上皮组织及NPC组织中的表达水平,利用癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库分析axl与头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSC)患者预后的关系,包括总生存时间(overall survival,OS)、无病生存期(disease-free interval,DFI)、疾病特异性生存期(disease-specific survival,DSS)及无进展生存期(progression-free interval,PFI)4个预后指标;采用蛋白质印迹法检测axl在正常鼻咽上皮细胞系及NPC细胞系中的蛋白质表达水平,免疫组织化学实验检测axl在正常鼻咽上皮组织及NPC组织中的表达;利用慢病毒干扰载体包装病毒感染5-8F和Fadu细胞建立稳定敲低axl的细胞系,利用慢病毒表达载体包装病毒感染C666-1和HK-1细胞建立稳定过表达axl的细胞系,并通过real-time PCR及蛋白质印迹法检测稳转细胞系的干扰和过表达效率;利用CCK-8、平板克隆形成实验及Transwell实验检测敲低或过表达axl对NPC细胞增殖、迁移及侵袭能力的影响,利用裸鼠皮下成瘤实验检测敲低axl对裸鼠体内肿瘤生长的影响;利用UCSC在线数据库查询并获取axl上游2.0 kb启动子区域的碱基序列,将序列输入PROMO在线数据库中以容错率0%为条件预测axl的转录因子,并利用JASPAR在线数据库预测ETS1与axl的结合位点;通过real-time PCR及蛋白质印迹法检测ETS1表达改变对axl蛋白及mRNA表达水平的影响;将axl上游2.0 kb启动子区域划分为8个片段,每个片段长度为250 bp,分别针对8个片段设计引物,利用染色质免疫沉淀(chromatin immunoprecipitation,ChIP)实验检测ETS1与axl启动子区域的结合,明确ETS1对axl的直接调控关系;利用功能回复实验检测ETS1是否通过axl影响NPC细胞的增殖、迁移及侵袭能力。结果:生物信息学分析发现axl在NPC组织中高表达(Paxl高表达与HNSC患者更短的OS、DFI、DSS及PFI呈正相关。蛋白质印迹及免疫组织化学实验结果显示:相对于正常鼻咽上皮细胞系及组织,axl在NPC细胞系及组织中高表达。Real-time PCR及蛋白质印迹实验结果显示:稳转细胞系的干扰及过表达效率满足后续实验要求。CCK-8、平板克隆形成实验、Transwell实验及裸鼠皮下成瘤实验结果表明:axl表达下调显著抑制NPC细胞的增殖、迁移、侵袭及肿瘤生长(均Paxl表达上调显著促进NPC细胞的增殖、迁移及侵袭(均Paxl的转录因子,且与axl启动子区域存在多个结合位点。Real-time PCR及蛋白质印迹法结果显示:敲低或过表达ETS1能够下调或上调axl蛋白及mRNA的表达水平。ChIP实验结果显示:ETS1能与axl的启动子区域结合,直接调控axl的表达。功能回复实验结果显示:axl能够回复ETS1对NPC细胞增殖、迁移及侵袭能力的影响(Paxl在NPC细胞系及组织中高表达,能促进NPC的恶性进展,其表达受转录因子ETS1的调控。

关键词：鼻咽癌 axl ETS1 增殖迁移侵袭

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axl Alleviates Neuroinflammation and Delays Japanese Encephalitis Progression in Mice

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Virologica Sinica 2021年第4期36卷 667-677页

作者： Zhao-Yang Wang Zi-Da Zhen Dong-Ying Fan Pei-Gang Wang Jing An Department of Microbiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Center of Epilepsy Beijing Institute for Brain DisordersBeijing 100093China

Japanese encephalitis virus(JEV)is a mosquito-borne flavivirus,which causes the most commonly diagnosed viral encephalitis named Japanese encephalitis(JE)in the world with an unclear pathogenesis.axl,a receptor tyrosine kinase from TAM family,plays crucial role in many inflammatory diseases.We have previously discovered that axl deficiency resulted in more severe body weight loss in mice during JEV infection,which we speculate is due to the anti-inflammatory effect of axl during JE.Currently,the role of axl in regulating the neuroinflammation and brain damage during JE has not been investigated yet.In this study,by using axl deficient and heterozygous control mice,we discovered that axl deficient mice displayed accelerated JE progression and exacerbated brain damage characterized by increased neural cell death,extended infiltration of inflammatory cells,and enhanced production of pro-inflammatory cytokines,in comparison to control mice.Additionally,consistent with our previous report,axl deficiency had no impact on the infection and target cell tropism of JEV in brain.Taken together,our results suggest that axl plays an anti-inflammatory and neuroprotective role during the pathogenesis of JE.

关键词： axl Japanese encephalitis virus(JEV) Inflammation Cytokine

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Japanese Encephalitis Virus NS2B-3 Protein Complex Promotes Cell Apoptosis and Viral Particle Release by Down-Regulating the Expression of axl

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Virologica Sinica 2021年第6期36卷 1503-1519页

作者： Shengda Xie Zhenjie Liang Xingmiao Yang Junhui Pan Du Yu Tongtong Li Ruibing Cao MOE Joint International Research Laboratory of Animal Health and Food Safety College of Veterinary MedicineNanjing Agricultural UniversityNanjing210095China

Japanese encephalitis virus(JEV) is a flavivirus transmitted by mosquitoes that causes severe encephalitis in humans and animals. It has been suggested that axl, a transmembrane protein, can promote the replication of various flaviviruses,such as dengue(DENV), Zika(ZIKV), and West Nile(WNV) viruses. However, the effect of axl on JEV infection has not yet been determined. In the present study, we demonstrate that axl is down-regulated after JEV infection in the late stage. JEV NS2B-3 protein specifically interacted with axl, and promoted axl degradation through the ubiquitin–proteasome pathway. axl-degradation increased cell apoptosis by disrupting phosphatidylinositol 3-kinase(PI3 K)/Akt signal transduction. In addition, the degradation of axl promoted JEV release to supernatant, whereas the virus in the cell lysates decreased. The supplementation of axl ligand Gas6 inhibited the JEV-mediated degradation of axl. Altogether,we discover a new function of NS2B-3 during the process of JEV replication, and provide a new insight into the interactions between JEV and cell hosts.

关键词： Japanese encephalitis virus(JEV) axl NS2B-3 Cell apoptosis Virus release

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The Multifaceted Roles of TAM Receptors during Viral Infection

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Virologica Sinica 2021年第1期36卷 1-12页

作者： Zhao-Yang Wang Pei-Gang Wang Jing An Department of Microbiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Center of Epilepsy Beijing Institute for Brain DisordersBeijing 100093China

Tyro3,axl,and Mertk(TAM)receptors play multiple roles in a myriad of physiological and pathological processes,varying from promoting the phagocytic clearance of apoptotic cells,sustaining the immune and inflammatory homeostasis,maintaining the blood-brain barrier(BBB)integrity and central nervous system(CNS)homeostasis,to mediating cancer malignancy and chemoresistance.Growth arrest-specific protein 6(Gas6)and protein S(Pros1)are the two ligands that activate TAM receptors.Recently,TAM receptors have been reported to mediate cell entry and infection of multitudinous enveloped viruses in a manner called apoptotic mimicry.Moreover,TAM receptors are revitalized during viral entry and infection,which sequesters innate immune and inflammatory responses,facilitating viral replication and immune evasion.However,accumulating evidence have now proposed that TAM receptors are not required for the infection of these viruses in vivo.In addition,TAM receptors protect mice against the CNS infection of neuroinvasive viruses and relieve the brain lesions during encephalitis.These protective effects are achieved through maintaining BBB integrity,attenuating proinflammatory cytokine production,and promoting neural cell survival.TAM receptors also regulate the programmed cell death modes of virus-infected cells,which have profound impacts on the pathogenesis and outcome of infection.Here,we systematically review the functionalities and underlying mechanisms of TAM receptors and propose the potential application of TAM agonists to prevent severe viral encephalitis.

关键词： axl Tyro3 Mertk Virus Infection

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Role of axl in invasion and drug resistance of colon and breast cancer cells and its association with p53 alterations

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World Journal of Gastroenterology 2017年第19期23卷 3440-3448页

作者： Wael M Abdel-Rahman Noura A Al-khayyal Vidhya A Nair S R Aravind Maha Saber-Ayad Department of Medical Laboratory Sciences College of Health Sciences and Sharjah Institute for Medical ResearchUniversity of Sharjah College of Medicine and Sharjah Institute for Medical Research University of Sharjah Environment and Cancer Research Group Sharjah Institute for Medical ResearchUniversity of Sharjah Department of Basic Medical Sciences College of Medicineand Sharjah Institute for medical ResearchUniversity of SharjahSharjah Cairo University

AIM To characterize axl receptor tyrosine kinase(axl)expression in relationship to tumor protein P53(TP53gene,p53 protein)and its role in tumor invasion and response to therapy.METHODS We used 14 cell lines,including 3 isogenic pairs carrying mutant/knockout p53,to gain insight into the relationship between axl and TP53.These included HCT116,HCT116.p53 mutant,RKO,and RKO.p53-/-lines(all from colon cancers)as well as breast cancer cell lines MCF7 and 1001(MCF7-p53 mutant clone).He La cell line was used as a positive control for epithelial to mesenchymal transition(EMT).axl expression was determined by Western blotting using rabbit monoclonal antibody clone C89E7.axl si RNA silencing was performed and followed by collagen invasion assay.Cell viability analysis using the sulforhodamine B assay and the invasion assay were performed after exposure to chemotherapeutic agents(doxorubicin for breast cancer cells;5FU or irinotecan for colon cancer cells).RESULTS We showed that the introduction of p53 mutations or knockout increased expression levels of axl in isogenic cells compared to the matching p53 wild-type parental cells.Overall,we found a trend for correlation between the potential EMT candidate axl,p53 alterations,and EMT markers in colorectal and breast cancers.The expression of axl in RKO cells,a rare colon cancer cell line with inactive Wnt signaling,suggests that the axl oncogene might provide an alternative genetic pathway for colorectal carcinogenesis in the absence of Wnt signaling activation and TP53 mutation.axl silencing in the TP53 mutant isogenic cell lines 1001,HCT116.p53 mutant and RKO.P53-/-was>95%efficient and the silenced cells were less invasive compared to the parental TP53 wild-type cells.axl silencing showed a subtle trend to restore colon cancer cell sensitivity to5FU or irinotecan.Importantly,axl expressing cells developed more invasive potential after exposure to chemotherapy compared to the axl-silenced cells.CONCLUSION axl is influenced by p53 status and could cause the emergence of aggre

关键词： axl 乳癌化疗结肠癌侵略

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ALKBH5调控axl mRNA去甲基化促进卵巢癌细胞化疗耐药性

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现代妇产科进展 2022年第12期31卷 896-901页

作者：吴世丽张燕许莉海口市妇幼保健院妇产科海口570102

目的:探索m^(6)A去甲基化酶ALKBH5调控受体酪氨酸激酶(axl)mRNA甲基化,增强卵巢癌细胞(SKOV3)迁移、增殖及耐药的作用机制。方法:利用CPTAC数据库分析ALKBH5蛋白在卵巢癌中的表达情况及其与总生存期的相关性。对SKOV3细胞过表达或敲低AL... 详细信息

目的:探索m^(6)A去甲基化酶ALKBH5调控受体酪氨酸激酶(axl)mRNA甲基化,增强卵巢癌细胞(SKOV3)迁移、增殖及耐药的作用机制。方法:利用CPTAC数据库分析ALKBH5蛋白在卵巢癌中的表达情况及其与总生存期的相关性。对SKOV3细胞过表达或敲低ALKBH5,CCK-8法、平板克隆法、划痕实验分别检测细胞的增殖、迁移和化疗药物耐药性;流式细胞术检测细胞凋亡;RNA稳定性实验检测ALKBH5过表达或敲低对axl mRNA降解的影响,以及axl敲低后对紫杉醇(paclitaxel)药物敏感性的影响。结果:ALKBH5蛋白在卵巢癌细胞和组织中高表达,而ALKBH5表达升高可能是卵巢癌患者生存率降低的独立预后因素。ALKBH5高表达增强了细胞的增殖和迁移能力。ALKBH5敲低后卵巢癌细胞凋亡率提高,axl mRNA降解半衰期下调。axl mRNA沉默后,卵巢癌细胞对紫杉醇的敏感性增加。结论:卵巢癌细胞中ALKBH5具有降低axl mRNA甲基化,稳定axl mRNA,保障axl功能的作用,进而强化了axl高表达对卵巢癌细胞的耐药性。

关键词：卵巢癌 ALKBH5 m^(6)A甲基化 axl

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