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MEG3 modulates TIGIT expression and CD4 + T cell activation through absorbing miR-23a

  • Jianhong Wang
  • Xiangxiang Liu
  • Caixia Hao
  • Yingjuan Lu
  • Xiaohui Duan
  • Rong Liang
  • Guangxun Gao
  • Tao Zhang
Article

Abstract

T cells are involved in bone marrow failure in aplastic anemia (AA). MEG3 is a long, non-coding RNA that can modulate target gene expression and T cell differentiation by acting as a microRNA sponge. Our previous study showed that T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif (ITIM) domain (TIGIT) plays a critical role in regulating CD4 + T cell functions. In this study, we found that MEG3 expression was significantly downregulated in CD4 + T cells derived from AA patients. MEG3 modulated CD4 + T cell proliferation and IFN-γ and TNF-α levels, as well as TIGIT, T-bet, and orphan nuclear receptor (RORγt) expression. Furthermore, MEG3 overexpression sequestered miR-23a and prompted TIGIT expression in CD4 + T cells. CD4 + T cells with MEG3 overexpression impeded expansion of Th1 and Th17 cells, restored the decreased red blood cell count, attenuated the increase in serum INF-γ and TNF-α levels, and lengthened median survival time, as well as upregulated mRNA levels of CD34, stem cell factor (SCF), and granulocyte/macrophage-colony-stimulating factor (GM-CSF) in bone marrow mononuclear cells of a mouse model. In conclusion, our study provides evidence that MEG3 regulated TIGIT expression and CD4 + T cell activation by absorbing miR-23a. These findings provide novel insight into autoimmune-mediated AA.

Keywords

MEG3 TIGIT CD4 + T cell MiR-23a Aplastic anemia 

Abbreviations

ITIM

T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif

TIGIT

T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain

RORγt

Orphan nuclear receptor

SCF

Stem cell factor

GM-CSF

Granulocyte/macrophage-colony-stimulating factor

AA

Aplastic anemia

BM

Bone marrow

Tregs

Regulatory T cells

lncRNAs

Long-chain non-coding RNAs

MEG3

Maternally expressed gene 3

Anti-NC

Anti-control

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

ELISA

Enzyme-linked immunosorbent assay

qRT-PCR

Quantitative real-time polymerase chain reaction

BMMNCs

Bone marrow mononuclear cells

RIPA

Radioimmunoprecipitation assay

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

IFN-γ

Interferon gamma

TNF-α

Tumor necrosis factor-a

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Lu SH, Ge ML, Zheng YZ, Yang SG, Chen F, You YH, Han ZC (2018) Effect of CD106(+) mesenchymal stem cell on bone marrow vascular failure in patients with aplastic anemia. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 40:178–186PubMedGoogle Scholar
  2. 2.
    Wu H, Miao M, Zhang G, Hu Y, Ming Z, Zhang X (2009) Soluble PD-1 is associated with aberrant regulation of T cells activation in aplastic anemia. Immunol Invest 38:408–421CrossRefGoogle Scholar
  3. 3.
    Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW, Smyth MJ, Kuchroo VK, Anderson AC (2015) TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 125:4053–4062CrossRefGoogle Scholar
  4. 4.
    Kourepini E, Paschalidis N, Simoes DC, Aggelakopoulou M, Grogan JL, Panoutsakopoulou V (2016) TIGIT enhances antigen-specific Th2 recall responses and allergic disease. J Immunol 196:3570–3580CrossRefGoogle Scholar
  5. 5.
    Samanta D, Guo H, Rubinstein R, Ramagopal UA, Almo SC (2017) Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2. Mol Immunol 81:151–159CrossRefGoogle Scholar
  6. 6.
    Xu J, Xu Y (2017) The lncRNA MEG3 downregulation leads to osteoarthritis progression via miR-16/SMAD7 axis. Cell Biosci 7:69CrossRefGoogle Scholar
  7. 7.
    Sethuraman S, Gay LA, Jain V, Haecker I, Renne R (2017) microRNA dependent and independent deregulation of long non-coding RNAs by an oncogenic herpesvirus. PLoS Pathog 13:e1006508CrossRefGoogle Scholar
  8. 8.
    Liu W, Liu X, Luo M, Luo Q, Tao H, Wu D, Lu S, Jin J, Zhao Y, Zou L (2017) dNK derived IFN-gamma mediates VSMC migration and apoptosis via the induction of LncRNA MEG3: a role in uterovascular transformation. Placenta 50:32–39CrossRefGoogle Scholar
  9. 9.
    Fan FY, Deng R, Yi H, Sun HP, Zeng Y, He GC, Su Y (2017) The inhibitory effect of MEG3/miR-214/AIFM2 axis on the growth of T-cell lymphoblastic lymphoma. Int J Oncol 51:316–326CrossRefGoogle Scholar
  10. 10.
    Yao H, Sun P, Duan M, Lin L, Pan Y, Wu C, Fu X, Wang H, Guo L, Jin T, Ding Y (2017) microRNA-22 can regulate expression of the long non-coding RNA MEG3 in acute myeloid leukemia. Oncotarget 8:65211–65217PubMedPubMedCentralGoogle Scholar
  11. 11.
    You L, Wang N, Yin D, Wang L, Jin F, Zhu Y, Yuan Q, De W (2016) Downregulation of long noncoding RNA Meg3 affects insulin synthesis and secretion in mouse pancreatic beta cells. J Cell Physiol 231:852–862CrossRefGoogle Scholar
  12. 12.
    Li W, Dong Y, Zhang B, Kang Y, Yang X, Wang H (2016) PEBP4 silencing inhibits hypoxia-induced epithelial-to-mesenchymal transition in prostate cancer cells. Biomed Pharmacother 81:1–6CrossRefGoogle Scholar
  13. 13.
    Zhang T, Wang J, Zhou X, Liang R, Bai Q, Yang L, Gu H, Gao G, Dong B, Zhu H, Chen X (2014) Increased expression of TIGIT on CD4 + T cells ameliorates immune-mediated bone marrow failure of aplastic anemia. J Cell Biochem 115:1918–1927PubMedGoogle Scholar
  14. 14.
    Hong Q, Li O, Zheng W, Xiao WZ, Zhang L, Wu D, Cai GY, He JC, Chen XM (2017) LncRNA HOTAIR regulates HIF-1alpha/AXL signaling through inhibition of miR-217 in renal cell carcinoma. Cell Death Dis 8:e2772CrossRefGoogle Scholar
  15. 15.
    Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation. Immunity 44:989–1004CrossRefGoogle Scholar
  16. 16.
    Li JQ, Hu SY, Wang ZY, Lin J, Jian S, Dong YC, Wu XF, Dai L, Cao LJ (2016) Long non-coding RNA MEG3 inhibits microRNA-125a-5p expression and induces immune imbalance of Treg/Th17 in immune thrombocytopenic purpura. Biomed Pharmacother 83:905–911CrossRefGoogle Scholar
  17. 17.
    Su W, Xie W, Shang Q, Su B (2015) The long noncoding RNA MEG3 is downregulated and inversely associated with VEGF levels in osteoarthritis. Biomed Res Int 2015:356893PubMedPubMedCentralGoogle Scholar
  18. 18.
    Hu J, Zhai C, Li Z, Fei H, Wang Z, Fan W (2017) MiR-23a inhibited IL-17-mediated proinflammatory mediators expression via targeting IKKalpha in articular chondrocytes. Int Immunopharmacol 43:1–6CrossRefGoogle Scholar
  19. 19.
    Fenoglio C, Ridolfi E, Cantoni C, De Riz M, Bonsi R, Serpente M, Villa C, Pietroboni AM, Naismith RT, Alvarez E, Parks BJ, Bresolin N, Cross AH, Piccio LM, Galimberti D, Scarpini E (2013) Decreased circulating miRNA levels in patients with primary progressive multiple sclerosis. Mult Scler J 19:1938–1942CrossRefGoogle Scholar
  20. 20.
    Lozano-Bartolome J, Llaurado G, Otin MP, Altuna-Coy A, Rojo-Martinez G, Vendrell J, Jorba R, Rodriguez-Gallego E, Chacon MR (2018) Altered expression of miR-181a-5p and miR-23a-3p is associated with obesity and TNFalpha-induced insulin resistance. J Clin Endocrinol Metab 103:1447CrossRefGoogle Scholar
  21. 21.
    Dixon KO, Schorer M, Nevin J, Etminan Y, Amoozgar Z, Kondo T, Kurtulus S, Kassam N, Sobel RA, Fukumura D, Jain RK, Anderson AC, Kuchroo VK, Joller N (2018) Functional anti-TIGIT antibodies regulate development of autoimmunity and antitumor immunity. J Immunol 200:3000–3007CrossRefGoogle Scholar
  22. 22.
    Zhao W, Dong Y, Wu C, Ma Y, Jin Y, Ji Y (2016) TIGIT overexpression diminishes the function of CD4 T cells and ameliorates the severity of rheumatoid arthritis in mouse models. Exp Cell Res 340:132–138CrossRefGoogle Scholar
  23. 23.
    Luo Q, Ye J, Zeng L, Li X, Fang L, Ju B, Huang Z, Li J (2017) Elevated expression of TIGIT on CD3(+)CD4(+) T cells correlates with disease activity in systemic lupus erythematosus. Allergy Asthma Clin Immunol 13:15CrossRefGoogle Scholar
  24. 24.
    Luo Q, Deng Z, Xu C, Zeng L, Ye J, Li X, Guo Y, Huang Z, Li J (2017) Elevated expression of immunoreceptor tyrosine-based inhibitory motif (TIGIT) on T lymphocytes is correlated with disease activity in rheumatoid arthritis. Med Sci Monit 23:1232–1241CrossRefGoogle Scholar
  25. 25.
    Mao L, Hou H, Wu S, Zhou Y, Wang J, Yu J, Wu X, Lu Y, Bosco MJ, Wang F, Sun Z (2017) TIGIT signalling pathway negatively regulates CD4(+) T-cell responses in systemic lupus erythematosus. Immunology 151:280–290CrossRefGoogle Scholar
  26. 26.
    Wu S, Zhou Y, Liu S, Zhang H, Luo H, Zuo X, Li T (2018) Regulatory effect of nicotine on the differentiation of Th1, Th2 and Th17 lymphocyte subsets in patients with rheumatoid arthritis. Eur J PharmacolGoogle Scholar
  27. 27.
    Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, Xia J, Tan TG, Sefik E, Yajnik V, Sharpe AH, Quintana FJ, Mathis D, Benoist C, Hafler DA, Kuchroo VK (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569–581CrossRefGoogle Scholar
  28. 28.
    Yao R, Ma YL, Liang W, Li HH, Ma ZJ, Yu X, Liao YH (2012) MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS ONE 7:e46082CrossRefGoogle Scholar
  29. 29.
    Li J, Ge M, Lu S, Shi J, Li X, Wang M, Huang J, Shao Y, Huang Z, Zhang J, Nie N, Zheng Y (2017) Pro-inflammatory effects of the Th1 chemokine CXCL10 in acquired aplastic anaemia. Cytokine 94:45–51CrossRefGoogle Scholar
  30. 30.
    Zhao W, Zhang Y, Zhang P, Yang J, Zhang L, He A, Zhang W, Hideto T (2017) High programmed death 1 expression on T cells in aplastic anemia. Immunol Lett 183:44–51CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jianhong Wang
    • 1
  • Xiangxiang Liu
    • 1
  • Caixia Hao
    • 1
  • Yingjuan Lu
    • 1
  • Xiaohui Duan
    • 1
  • Rong Liang
    • 1
  • Guangxun Gao
    • 1
  • Tao Zhang
    • 1
  1. 1.Department of Hematology, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina

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