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Construction of lncRNA-Mediated ceRNA Network for Investigating Immune Pathogenesis of Ischemic Stroke

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Abstract

Ischemic stroke (IS) is a common and serious neurological disease. Extensive evidence indicates that activation of the immune system contributes significantly to the development of IS pathology. In recent years, some long non-coding RNAs (lncRNAs), acting as competing endogenous RNAs (ceRNAs), have been reported to affect IS process, especially the immunological response after stroke. However, the roles of lncRNA-mediated ceRNAs in immune pathogenesis of IS are not systemically investigated. In the present study, we generated a global immune-related ceRNA network containing immune-related genes (IRGs), miRNAs, and lncRNAs based on experimentally verified interactions. Further, we excavated an IS immune-related ceRNA (ISIRC) network through mapping significantly differentially expressed IRGs, miRNAs, and lncRNAs of patients with IS into the global network. We analyzed the topological properties of the two networks, respectively, and found that lncRNA NEAT1 and lncRNA KCNQ1OT1 played core roles in aforementioned two immune-related networks. Moreover, the results of functional enrichment analyses revealed that lncRNAs in the ISIRC network were mainly involved in several immune-related biological processes and pathways. Finally, we identified 17 lncRNAs which were highly related to the immune mechanism of IS through performing random walk with restart for the ISIRC network. Importantly, it has been confirmed that NEAT1, KCNQ1OT1, GAS5, and RMRP could regulate immuno-inflammatory response after stroke, such as production of inflammatory factors and activation of the immune cells. Our results suggested that lncRNAs exerted an important role in the immune pathogenesis of IS and provided a new strategy to do research on IS.

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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Deb P, Sharma S, Hassan KM (2010) Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 17(3):197–218. https://doi.org/10.1016/j.pathophys.2009.12.001

    Article  CAS  PubMed  Google Scholar 

  2. Dziedzic T (2015) Systemic inflammation as a therapeutic target in acute ischemic stroke. Expert Rev Neurother 15(5):523–531. https://doi.org/10.1586/14737175.2015.1035712

    Article  CAS  PubMed  Google Scholar 

  3. Kawabori M, Yenari MA (2015) Inflammatory responses in brain ischemia. Curr Med Chem 22:1258–1277. https://doi.org/10.2174/0929867322666150209154036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tuttolomondo A, Pinto A, Corrao S, Di Raimondo D, Fernandez P, Di Sciacca R, Arnao V, Licata G (2009) Immuno-inflammatory and thrombotic/fibrinolytic variables associated with acute ischemic stroke diagnosis. Atherosclerosis 203(2):503–508. https://doi.org/10.1016/j.atherosclerosis.2008.06.030

    Article  CAS  PubMed  Google Scholar 

  5. Sun M, Deng B, Zhao X, Gao C, Yang L, Zhao H, Yu D, Zhang F et al (2015) Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation. Sci Rep 5(1). https://doi.org/10.1038/srep11445

  6. Emmrich JV, Ejaz S, Neher JJ, Williamson DJ, Baron J-C (2014) Regional distribution of selective neuronal loss and microglial activation across the MCA territory after transient focal ischemia: quantitative versus semiquantitative systematic immunohistochemical assessment. J Cereb Blood Flow Metab 35(1):20–27. https://doi.org/10.1038/jcbfm.2014.181

    Article  PubMed  PubMed Central  Google Scholar 

  7. Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, Dengler R, Lichtinghagen R et al (2010) The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 30(1):85–92. https://doi.org/10.1159/000314624

    Article  CAS  PubMed  Google Scholar 

  8. Vila N, Castillo J, Dávalos A, Chamorro A (2000) Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31:2325–2329. https://doi.org/10.1161/01.str.31.10.2325

    Article  CAS  PubMed  Google Scholar 

  9. Acalovschi D, Wiest T, Hartmann M, Farahmi M, Mansmann U, Auffarth GU, Grau AJ, Green FR et al (2003) Multiple levels of regulation of the interleukin-6 system in stroke. Stroke 34:1864–1869. https://doi.org/10.1161/01.STR.0000079815.38626.44

    Article  CAS  PubMed  Google Scholar 

  10. Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi Pier P (2011) A ceRNA hypothesis: the rosetta stone of a hidden RNA language? Cell 146(3):353–358. https://doi.org/10.1016/j.cell.2011.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sheng Y, Ma J, Zhao J, Qi S, Hu R, Yang Q (2019) Differential expression patterns of specific long noncoding RNAs and competing endogenous RNA network in alopecia areata. J Cell Biochem 120(6):10737–10747. https://doi.org/10.1002/jcb.28365

    Article  CAS  PubMed  Google Scholar 

  12. Li H, Wang M, Zhou H, Lu S, Zhang B (2020) Long noncoding RNA EBLN3P promotes the progression of liver cancer via alteration of microRNA-144-3p/DOCK4 signal. Cancer Manag Res 12:9339–9349. https://doi.org/10.2147/cmar.S261976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Luan X, Wang Y (2018) LncRNA XLOC_006390 facilitates cervical cancer tumorigenesis and metastasis as a ceRNA against miR-331-3p and miR-338-3p. J Gynecol Oncol 29(6). https://doi.org/10.3802/jgo.2018.29.e95

  14. Yan H, Rao J, Yuan J, Gao L, Huang W, Zhao L, Ren J (2017) Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway. Cell Death Dis 8(12):3211. https://doi.org/10.1038/s41419-017-0047-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dang S, Malik A, Chen J, Qu J, Yin K, Cui L, Gu M (2020) LncRNA SNHG15 contributes to immuno-escape of gastric cancer through targeting miR141/PD-L1. Onco Targets Ther 13:8547–8556. https://doi.org/10.2147/ott.S251625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yan S, Wang P, Wang J, Yang J, Lu H, Jin C, Cheng M, Xu D (2019) Long non-coding RNA HIX003209 promotes inflammation by sponging miR-6089 via TLR4/NF-κB signaling pathway in rheumatoid arthritis. Front Immunol 10. https://doi.org/10.3389/fimmu.2019.02218

  17. Cao D-w, Liu M-m, Duan R, Tao Y-f, Zhou J-s, Fang W-r, Zhu J-r, Niu L et al (2019) The lncRNA Malat1 functions as a ceRNA to contribute to berberine-mediated inhibition of HMGB1 by sponging miR-181c-5p in poststroke inflammation. Acta Pharmacol Sin 41(1):22–33. https://doi.org/10.1038/s41401-019-0284-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vlachos IS, Paraskevopoulou MD, Karagkouni D, Georgakilas G, Vergoulis T, Kanellos I, Anastasopoulos I-L, Maniou S et al (2015) DIANA-TarBase v7.0: indexing more than half a million experimentally supported miRNA:mRNA interactions. Nucleic Acids Res 43(D1):D153–D159. https://doi.org/10.1093/nar/gku1215

    Article  CAS  PubMed  Google Scholar 

  19. Li J-H, Liu S, Zhou H, Qu L-H, Yang J-H (2014) starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res 42(D1):D92–D97. https://doi.org/10.1093/nar/gkt1248

    Article  CAS  PubMed  Google Scholar 

  20. Breuer K, Foroushani AK, Laird MR, Chen C, Sribnaia A, Lo R, Winsor GL, Hancock REW et al (2013) InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curation. Nucleic Acids Res 41(D1):D1228–D1233. https://doi.org/10.1093/nar/gks1147

    Article  CAS  PubMed  Google Scholar 

  21. Bhattacharya S, Andorf S, Gomes L, Dunn P, Schaefer H, Pontius J, Berger P, Desborough V et al (2014) ImmPort: disseminating data to the public for the future of immunology. Immunol Res 58(2-3):234–239. https://doi.org/10.1007/s12026-014-8516-1

    Article  CAS  PubMed  Google Scholar 

  22. Zhu W, Tian L, Yue X, Liu J, Fu Y, Yan Y (2019) LncRNA expression profiling of ischemic stroke during the transition from the acute to subacute stage. Front Neurol 10. https://doi.org/10.3389/fneur.2019.00036

  23. Li S, Zheng H, Chen L, Xu C, Qu X, Qin Z, Gao J, Li J et al (2019) Expression profile and potential functions of circulating long noncoding RNAs in acute ischemic stroke in the Southern Chinese Han population. Front Mol Neurosci 12:290. https://doi.org/10.3389/fnmol.2019.00290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, Aken BL, Barrell D et al (2012) GENCODE: the reference human genome annotation for the ENCODE Project. Genome Res 22(9):1760–1774. https://doi.org/10.1101/gr.135350.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yu G, Wang L-G, Han Y, He Q-Y (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS J Integr Biol 16(5):284–287. https://doi.org/10.1089/omi.2011.0118

    Article  CAS  Google Scholar 

  26. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT et al (2019) STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47(D1):D607–D613. https://doi.org/10.1093/nar/gky1131

    Article  CAS  PubMed  Google Scholar 

  27. Rochet E, Appukuttan B, Ma Y, Ashander LM, Smith JR (2019) Expression of long non-coding RNAs by human retinal Müller glial cells infected with clonal and exotic virulent toxoplasma gondii. Non-Coding RNA 5(4). https://doi.org/10.3390/ncrna5040048

  28. Liu R, Tang A, Wang X, Chen X, Zhao L, Xiao Z, Shen S (2018) Inhibition of lncRNA NEAT1 suppresses the inflammatory response in IBD by modulating the intestinal epithelial barrier and by exosome-mediated polarization of macrophages. Int J Mol Med. https://doi.org/10.3892/ijmm.2018.3829

  29. Zhang Y, Zhu Y, Gao G, Zhou Z (2019) Knockdown XIST alleviates LPS-induced WI-38 cell apoptosis and inflammation injury via targeting miR-370-3p/TLR4 in acute pneumonia. Cell Biochem Funct 37(5):348–358. https://doi.org/10.1002/cbf.3392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA (2019) Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation 16(1):142. https://doi.org/10.1186/s12974-019-1516-2

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ni X, Su Q, Xia W, Zhang Y, Jia K, Su Z, Li G (2020) Knockdown lncRNA NEAT1 regulates the activation of microglia and reduces AKT signaling and neuronal apoptosis after cerebral ischemic reperfusion. Sci Rep 10(1):19658. https://doi.org/10.1038/s41598-020-71411-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang H-J, Tang X-L, Huang G, Li Y-B, Pan R-H, Zhan J, Wu Y-K, Liang J-F et al (2020) Long non-coding KCNQ1OT1 promotes oxygen-glucose-deprivation/reoxygenation-induced neurons injury through regulating MIR-153-3p/FOXO3 axis. J Stroke Cerebrovasc Dis 29(10):105126. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105126

    Article  PubMed  Google Scholar 

  33. Kollikowski AM, Schuhmann MK, Nieswandt B, Müllges W, Stoll G, Pham M (2020) Local leukocyte invasion during hyperacute human ischemic stroke. Ann Neurol 87(3):466–479. https://doi.org/10.1002/ana.25665

    Article  CAS  PubMed  Google Scholar 

  34. Guo Y, Chen X, Li D, Liu H, Ding Y, Han R, Shi Y, Ma X (2018) PR-957 mediates neuroprotection by inhibiting Th17 differentiation and modulating cytokine production in a mouse model of ischaemic stroke. Clin Exp Immunol 193(2):194–206. https://doi.org/10.1111/cei.13132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang J, Zhao H, Fan Z, Li G, Ma Q, Tao Z, Wang R, Feng J et al (2017) Long noncoding RNA H19 promotes neuroinflammation in ischemic stroke by driving histone deacetylase 1–dependent M1 microglial polarization. Stroke 48(8):2211–2221. https://doi.org/10.1161/strokeaha.117.017387

    Article  CAS  PubMed  Google Scholar 

  36. Wang Y, Luo Y, Yao Y, Ji Y, Feng L, Du F, Zheng X, Tao T et al (2019) Silencing the lncRNA Maclpil in pro-inflammatory macrophages attenuates acute experimental ischemic stroke via LCP1 in mice. J Cereb Blood Flow Metab 40(4):747–759. https://doi.org/10.1177/0271678x19836118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhu B, Cheng X, Jiang Y, Cheng M, Chen L, Bao J, Tang X (2020) Silencing of KCNQ1OT1 decreases oxidative stress and pyroptosis of renal tubular epithelial cells. Diabetes Metab Syndr Obes 13:365–375. https://doi.org/10.2147/dmso.S225791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li P, Duan S, Fu A (2019) Long noncoding RNA NEAT1 correlates with higher disease risk, worse disease condition, decreased miR-124 and miR-125a and predicts poor recurrence-free survival of acute ischemic stroke. J Clin Lab Anal 34(2):e23056. https://doi.org/10.1002/jcla.23056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I (2018) Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173(5):1073–1081. https://doi.org/10.1016/j.cell.2018.05.003

    Article  CAS  PubMed  Google Scholar 

  40. Yi M, Li Y, Wang D, Zhang Q, Yang L, Yang C (2020) KCNQ1OT1 exacerbates ischemia–reperfusion injury through targeted inhibition of miR-140-3P. Inflammation 43(5):1832–1845. https://doi.org/10.1007/s10753-020-01257-2

    Article  CAS  PubMed  Google Scholar 

  41. Zhang H, Lu M, Zhang X, Kuai Y, Mei Y, Tan Q, Zhong K, Sun X et al (2019) Isosteviol sodium protects against ischemic stroke by modulating microglia/macrophage polarization via disruption of GAS5/miR-146a-5p sponge. Sci Rep 9(1):12221. https://doi.org/10.1038/s41598-019-48759-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li X, Sui Y (2020) Valproate improves middle cerebral artery occlusion-induced ischemic cerebral disorders in mice and oxygen-glucose deprivation-induced injuries in microglia by modulating RMRP/PI3K/Akt axis. Brain Res 1747:147039. https://doi.org/10.1016/j.brainres.2020.147039

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by grants from the National Natural Science Foundation of China (nos. 81820108014, 81771361, 82071407, 81801190, and 81901277), National Key Research and Development Project (no. 2018YFE0114400), and the Postdoctoral Foundation of Heilongjiang Province (no. LBH-TZ1019).

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Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China

    Shuang Li, Huixue Zhang, Xiaoyu Lu, Tianfeng Wang, Si Xu, Tongxiao Kong, Chunrui Bo, Lifang Li, Jianjian Wang & Lihua Wang

  2. Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China

    Yuze Cao

  3. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, Heilongjiang Province, China

    Shangwei Ning

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  1. Shuang Li
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  2. Yuze Cao
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Contributions

All authors have participated in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. WL and CY are responsible of the part of the design of the work. LL, XS, and WT contributed to the part of acquisition and analysis of data. ZH and LX contributed to the part of interpretation of data. KX and BC are responsible of the creation of new software used in the work. LS, WJ, and NS have been involved in drafting the manuscript and revising it critically. All authors read and approved the final manuscript.

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Correspondence to Shangwei Ning, Jianjian Wang or Lihua Wang.

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Supplementary Information

Supplementary table 1

The results of GO function enrichment based on DEIRGs regulated by DElncRNAs in the ISIRC network (XLS 124 kb)

Supplementary table 2

The results of KEGG enrichment analysis based on DEIRGs regulated by DElncRNAs in the ISIRC network (XLS 24 kb)

Supplementary table 3

The detailed interactions among DEIRGs, DEmiRNAs and candidate DElncRNAs (XLS 27 kb)

Supplementary table 4

The DElncRNAs in GSE140275 (XLSX 90 kb)

Supplementary Figure 1

Venn diagram of 17 candidate DElncRNAs and GSE140275; yellow ellipse indicates 17 candidate DElncRNAs, purple ellipse indicates DElncRNAs of GSE140275; overlap intersection indicates common shared DElncRNAs. (PNG 161 kb)

High resolution image (TIF 2219 kb)

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Li, S., Cao, Y., Zhang, H. et al. Construction of lncRNA-Mediated ceRNA Network for Investigating Immune Pathogenesis of Ischemic Stroke. Mol Neurobiol 58, 4758–4769 (2021). https://doi.org/10.1007/s12035-021-02426-6

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