白细胞介素-17信号通路在锰中毒及相关的神经退行性疾病中作用的生物信息学研究  

Bioinformatics study on role of IL-17 signaling in manganese poisoning and manganese-related neurodegenerative diseases

作　　者：张钧柔 张诗玄 李婕 牛丕业 ZHANG Junrou;ZHANG Shixuan;LI Jie;NIU Piye(School of Public Health/Beijing Key Laboratory of Environmental Toxicology,Capital Medical University,Beijing 100069,China)

机构地区：[1]首都医科大学,公共卫生学院/环境毒理学北京市重点实验室,北京100069

出　　处：《环境与职业医学》2022年第10期1140-1145,共6页Journal of Environmental and Occupational Medicine

基　　金：国家自然科学基金项目:(81973007,82103797)。

摘　　要：[背景]锰(Mn)是帕金森病(PD)的环境致病因素之一,长期接触Mn会造成神经损伤。挖掘Mn的神经毒性作用与神经退行性疾病(NDD)尤其是PD的共同机制,对于疾病早期诊断具有重要意义。[目的]通过生物信息学综合分析NDD患者脑组织额叶皮质和Mn暴露的神经细胞中共表达的信使RNA(mRNA)-微小RNA(miRNA),揭示NDD尤其是PD与Mn的神经毒性作用的潜在共同机制。[方法]运用R软件对GSE150696数据库中NDD患者额叶皮质mRNAs和Mn染毒的人神经母细胞瘤细胞(SH-SY5Y)mRNAs进行差异分析;对重叠的差异表达基因(DEGs)进行京都基因与基因组百科全书(KEGG)通路分析。使用miRNet数据库预测miRNAs,通过starBase和miRTarBase数据库鉴定mRNA-miRNA相互作用关系,用Cytoscape软件构建mRNA-miRNA调控网络。通过加权基因共表达网络分析(WGCNA)聚类GSE77667数据库中与PD关联的核心miRNAs,并对比分析mRNA-miRNA调控网络。[结果]在NDD患者额叶皮质和Mn染毒神经细胞中共鉴定出34个重叠的DEGs,主要富集在白细胞介素-17(IL-17)信号通路、环磷酸腺苷(cAMP)信号通路、原发性免疫缺陷等通路。根据数据库预测结果,最终纳入52个miRNAs,共71对miRNA-mRNA相互作用关系构建调控网络。WGCNA筛选出6个核心miRNAs:hsa-let-7 i-5p、hsa-mir-155-5p、hsa-mir-219-2-3p、hsa-mir-221-3p、hsa-mir-485-3p和hsa-mir-509-3-5p;其中hsa-let-7 i-5p和hsa-mir-155-5p对应的靶基因分别为FBXW2和CCL2。KEGG分析结果提示CCL2与IL-17信号通路密切相关。[结论]NDD与Mn的神经毒性存在相似的分子调控机制,IL-17信号通路可能通过CCL2和hsa-mir-155-5p在Mn相关的NDD中发挥作用。[Background]Manganese(Mn)is one of the environmental factors of Parkinson's disease(PD),and long-term exposure to Mn can cause nerve damage.It is important to explore the common mechanism of neurotoxic effects of Mn and neurodegenerative diseases(NDD),especially PD,for early diagnosis of the disease.[Objective]To comprehensively analyze the core messenger RNA(mRNA)-microRNAs(miRNAs)co-expressed in frontal cortex of NDD patients and neuronal cells exposed to Mn via bioinformatics,and to reveal the potential common mechanism between Mn-induced neurotoxicity and NDD,especially PD.[Methods]Difference of the mRNAs from frontal cortex of NDD patients(GSE150696)and human neuroblastoma(SH-SY5Y)cells exposed to Mn were analyzed by R software;Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis was performed on the overlapping differentially expressed genes(DEGs).The miRNAs were predicted using the miRNet database,mRNA-miRNA interactions were identified by the starBase and miRTarBase databases,and mRNA-miRNA regulatory networks were constructed with Cytoscape software.The core miRNAs associated with PD(GSE77667)were incorporated into Weighted Gene Co-Expression Network Analysis(WGCNA)and the mRNA-miRNA regulatory network was comparatively analyzed.[Results]A total of 34 overlapping DEGs were identified in the frontal cortical of NDD patients and the neuronal cells exposed to Mn,mainly enriched in interleukin-17(IL-17)signaling pathway,cyclic adenosine monophosphate(cAMP)signaling pathway,and primary immunodeficiency.Based on the results of database prediction,52 miRNAs with 71 pairs of interaction relationships were finally included to construct the miRNA-mRNA regulatory network.Six core miRNAs were screened by WGCNA:hsa-let-7i-5p,hsa-mir-155-5p,hsa-mir-219-2-3p,hsa-mir-221-3p,hsa-mir-485-3p,and hsa-mir-509-3-5p,among which hsa-let-7i-5p interacted with the target gene FBXW2 and hsa-mir-155-5p interacted with the target gene CCL2.The results of the KEGG analysis indicated that CCL2 was closely related to the IL-17

关 键 词：锰 神经毒性 神经退行性疾病 帕金森病 作用机制 

分 类 号：R114[医药卫生—卫生毒理学]