Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

ALKBH5 Expression could Affect the Function of T Cells in Systemic Lupus Erythematosus Patients: A Case-control Study

Author(s): Li-Jun Deng, Xin-Yu Fang, Jun Wu, Qing-Ru Li, Yan-Mei Mao, Rui-Xue Leng, Yin-Guang Fan* and Dong-Qing Ye*

Volume 28, Issue 27, 2022

Published on: 12 August, 2022

Page: [2270 - 2278] Pages: 9

DOI: 10.2174/1381612828666220617154204

Price: $65

Abstract

Background: N6-methyladenosine (m6A) modification is widespread in eukaryotic mRNA, regulated by m6A demethylase, AlkB homolog 5 (ALKBH5). However, the role of m6A in systemic lupus erythematosus (SLE) is still obscure. We explored ALKBH5 expression in SLE patients and its effects on T cells.

Methods: 100 SLE patients and 110 healthy controls were recruited to investigate the expression of ALKBH5 in peripheral blood mononuclear cells (PBMCs). An additional 32 SLE patients and 32 health controls were enrolled to explore the expression of ALKBH5 in T cells. Then we explored the function of ALKBH5 in T cells by lentivirus.

Results: The expressions of ALKBH5 were downregulated in both PBMCs and T cells in SLE patients (all P<0.05). In PBMCs: ALKBH5 mRNA levels were associated with a complement C4 level in plasma (P<0.05). In T cells: ALKBH5 mRNA levels were downregulated in SLE patients with low complement levels, high antidsDNA, anti-Sm, anti-RNP, and proteinuria compared with those without, respectively (all P<0.05); ALKBH5 mRNA levels were negatively related with SLE disease activity index score, erythrocyte sedimentation rate, and anti-dsDNA levels (all P<0.05), and positively correlated with complement C3 and C4 level (all P<0.05). Functionally, the overexpression of ALKBH5 promoted apoptosis and inhibited the proliferation of T cells (all P<0.05).

Conclusion: ALKBH5 expression is downregulated in SLE patients and could affect the apoptosis and proliferation of T cells, but the exact mechanism still needs to be further explored.

Keywords: N6-methyladenosine, ALKBH5, peripheral blood mononuclear cells, T cells, systemic lupus erythematosus, case-control study.

« Previous
[1]
Kiriakidou M, Ching CL. Systemic lupus erythematosus. Ann Intern Med 2020; 172(11): ITC81-96.
[http://dx.doi.org/10.7326/AITC202006020] [PMID: 32479157]
[2]
Kuhn A, Bonsmann G, Anders HJ, Herzer P, Tenbrock K, Schneider M. The diagnosis and treatment of systemic lupus erythematosus. Dtsch Arztebl Int 2015; 112(25): 423-32.
[http://dx.doi.org/10.3238/arztebl.2015.0423] [PMID: 26179016]
[3]
Mistry P, Nakabo S, O’Neil L, et al. Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci USA 2019; 116(50): 25222-8.
[http://dx.doi.org/10.1073/pnas.1908576116] [PMID: 31754025]
[4]
Breitbach ME, Ramaker RC, Roberts K, Kimberly RP, Absher D. Population-specific patterns of epigenetic defects in the β cell lineage in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2020; 72(2): 282-91.
[http://dx.doi.org/10.1002/art.41083] [PMID: 31430064]
[5]
Li LJ, Zhao W, Tao SS, et al. Comprehensive long non-coding RNA expression profiling reveals their potential roles in systemic lupus erythematosus. Cell Immunol 2017; 319: 17-27.
[http://dx.doi.org/10.1016/j.cellimm.2017.06.004] [PMID: 28622785]
[6]
Wang J, Li Y, Wang P, et al. Leukemogenic chromatin alterations promote AML leukemia stem cells via a KDM4C-ALKBH5-AXL signaling axis. Cell Stem Cell. 2020; 27(1): 81-97.e8.
[http://dx.doi.org/10.1016/j.stem.2020.04.001] [PMID: 32402251]
[7]
Li LJ, Fan YG, Leng RX, Pan HF, Ye DQ. Potential link between m6A modification and systemic lupus erythematosus. Mol Immunol 2018; 93: 55-63.
[http://dx.doi.org/10.1016/j.molimm.2017.11.009] [PMID: 29145159]
[8]
Shi H, Wei J, He C. Where, when, and how: Context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell 2019; 74(4): 640-50.
[http://dx.doi.org/10.1016/j.molcel.2019.04.025] [PMID: 31100245]
[9]
Ping XL, Sun BF, Wang L, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 2014; 24(2): 177-89.
[http://dx.doi.org/10.1038/cr.2014.3] [PMID: 24407421]
[10]
Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 2011; 7(12): 885-7.
[http://dx.doi.org/10.1038/nchembio.687] [PMID: 22002720]
[11]
Zheng G, Dahl JA, Niu Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 2013; 49(1): 18-29.
[http://dx.doi.org/10.1016/j.molcel.2012.10.015] [PMID: 23177736]
[12]
Ueda Y, Ooshio I, Fusamae Y, et al. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells. Sci Rep 2017; 7: 42271.
[http://dx.doi.org/10.1038/srep42271] [PMID: 28205560]
[13]
Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell 2015; 162(6): 1299-308.
[http://dx.doi.org/10.1016/j.cell.2015.08.011] [PMID: 26321680]
[14]
Liu N, Dai Q, Zheng G, He C, Parisien M, Pan TN. (6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 2015; 518(7540): 560-4.
[http://dx.doi.org/10.1038/nature14234] [PMID: 25719671]
[15]
Huang H, Weng H, Sun W, et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 2018; 20(3): 285-95.
[http://dx.doi.org/10.1038/s41556-018-0045-z] [PMID: 29476152]
[16]
Yue B, Song C, Yang L, et al. METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer 2019; 18(1): 142.
[http://dx.doi.org/10.1186/s12943-019-1065-4] [PMID: 31607270]
[17]
Zhong L, He X, Song H, et al. METTL3 induces AAA development and progression by modulating N6-methyladenosine-dependent primary miR34a processing. Mol Ther Nucleic Acids 2020; 21: 394-411.
[http://dx.doi.org/10.1016/j.omtn.2020.06.005] [PMID: 32650237]
[18]
Shulman Z, Stern-Ginossar N. The RNA modification N6-methyladenosine as a novel regulator of the immune system. Nat Immunol 2020; 21(5): 501-12.
[http://dx.doi.org/10.1038/s41590-020-0650-4] [PMID: 32284591]
[19]
Du T, Rao S, Wu L, et al. An association study of the m6A genes with major depressive disorder in Chinese Han population. J Affect Disord 2015; 183: 279-86.
[http://dx.doi.org/10.1016/j.jad.2015.05.025] [PMID: 26047305]
[20]
Livneh I, Moshitch-Moshkovitz S, Amariglio N, Rechavi G, Dominissini D. The m6A epitranscriptome: Transcriptome plasticity in brain development and function. Nat Rev Neurosci 2020; 21(1): 36-51.
[http://dx.doi.org/10.1038/s41583-019-0244-z] [PMID: 31804615]
[21]
Lin X, Chai G, Wu Y, et al. RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun 2019; 10(1): 2065.
[http://dx.doi.org/10.1038/s41467-019-09865-9] [PMID: 31061416]
[22]
Rubio RM, Depledge DP, Bianco C, Thompson L, Mohr I. RNA m6 A modification enzymes shape innate responses to DNA by regulating interferon β. Genes Dev 2018; 32(23-24): 1472-84.
[http://dx.doi.org/10.1101/gad.319475.118] [PMID: 30463905]
[23]
Li HB, Tong J, Zhu S, et al. m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 2017; 548(7667): 338-42.
[http://dx.doi.org/10.1038/nature23450] [PMID: 28792938]
[24]
Li N, Kang Y, Wang L, et al. ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc Natl Acad Sci 2020; 117(33): 20159-70.
[http://dx.doi.org/10.1073/pnas.1918986117] [PMID: 32747553]
[25]
Luo Q, Rao J, Zhang L, et al. The study of METTL14, ALKBH5, and YTHDF2 in peripheral blood mononuclear cells from systemic lupus erythematosus. Mol Genet Genomic Med 2020; 8(9): e1298.
[http://dx.doi.org/10.1002/mgg3.1298] [PMID: 32583611]
[26]
Luo Q, Fu B, Zhang L, et al. Decreased peripheral blood ALKBH5 correlates with markers of autoimmune response in systemic lupus erythematosus. Dis Markers 2018; 2020: 8193895.
[27]
Finzel S, Schaffer S, Rizzi M, Voll RE. Pathogenesis of systemic lupus erythematosus. Z Rheumatol 2018; 77(9): 789-98.
[http://dx.doi.org/10.1007/s00393-018-0541-3] [PMID: 30291433]
[28]
Shlomchik MJ, Craft JE, Mamula MJ. From T to B and back again: Positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001; 1(2): 147-53.
[http://dx.doi.org/10.1038/35100573] [PMID: 11905822]
[29]
Dossybayeva K, Abdukhakimova D, Poddighe D. Basophils and systemic lupus erythematosus in murine models and human patients. Biology 2020; 9(10): 308.
[http://dx.doi.org/10.3390/biology9100308] [PMID: 32977704]
[30]
Hamilton JA, Hsu HC, Mountz JD. Autoreactive B cells in SLE, villains or innocent bystanders? Immunol Rev 2019; 292(1): 120-38.
[http://dx.doi.org/10.1111/imr.12815] [PMID: 31631359]
[31]
Ruhland MK, Roberts EW, Cai E, et al. Visualizing synaptic transfer of tumor antigens among dendritic cells. Cancer Cell 2020; 37(6): 786-799.e5.
[http://dx.doi.org/10.1016/j.ccell.2020.05.002] [PMID: 32516589]
[32]
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40(9): 1725.
[http://dx.doi.org/10.1002/art.1780400928] [PMID: 9324032]
[33]
Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002; 29(2): 288-91.
[PMID: 11838846]
[34]
Seth A, Craft J. Spatial and functional heterogeneity of follicular helper T cells in autoimmunity. Curr Opin Immunol 2019; 61: 1-9.
[http://dx.doi.org/10.1016/j.coi.2019.06.005] [PMID: 31374450]
[35]
Apostolidis SA, Lieberman LA, Kis-Toth K, Crispín JC, Tsokos GC. The dysregulation of cytokine networks in systemic lupus erythematosus. J Interferon Cytokine Res 2011; 31(10): 769-79.
[http://dx.doi.org/10.1089/jir.2011.0029] [PMID: 21877904]
[36]
Zhang D, Wang M, Shi G, Pan P, Ji J, Li P. Regulating T cell population alleviates SLE by inhibiting mTORC1/C2 in MRL/lpr mice. Front Pharmacol 2021; 11: 579298.
[http://dx.doi.org/10.3389/fphar.2020.579298] [PMID: 33597869]
[37]
Sánchez-Guerrero J, Lew RA, Fossel AH, Schur PH. Utility of anti-Sm, anti-RNP, anti-Ro/SS-A, and anti-La/SS-B (extractable nuclear antigens) detected by enzyme-linked immunosorbent assay for the diagnosis of systemic lupus erythematosus. Arthritis Rheum 1996; 39(6): 1055-61.
[http://dx.doi.org/10.1002/art.1780390626] [PMID: 8651971]
[38]
Janwityanuchit S, Verasertniyom O, Vanichapuntu M, Vatanasuk M. Anti-Sm: Its predictive value in systemic lupus erythematosus. Clin Rheumatol 1993; 12(3): 350-3.
[http://dx.doi.org/10.1007/BF02231577] [PMID: 8258234]
[39]
Pan N, Amigues I, Lyman S, et al. A surge in anti-dsDNA titer predicts a severe lupus flare within six months. Lupus 2014; 23(3): 293-8.
[http://dx.doi.org/10.1177/0961203313515763] [PMID: 24316605]
[40]
Liang Y, Leng RX, Pan HF, Ye DQ. Effects of disease activity and inflammatory response on hypercoagulability in patients with systemic lupus erythematosus. Arch Med Res 2016; 47(7): 573-9.
[http://dx.doi.org/10.1016/j.arcmed.2016.12.001] [PMID: 28262199]
[41]
Schur PH, Sandson J. Immunologic factors and clinical activity in systemic lupus erythematosus. N Engl J Med 1968; 278(10): 533-8.
[http://dx.doi.org/10.1056/NEJM196803072781004] [PMID: 4866347]
[42]
Weinstein A, Bordwell B, Stone B, Tibbetts C, Rothfield NF. Antibodies to native DNA and serum complement (C3) levels. Application to diagnosis and classification of systemic lupus erythematosus. Am J Med 1983; 74(2): 206-16.
[http://dx.doi.org/10.1016/0002-9343(83)90613-7] [PMID: 6600582]
[43]
Vaughan JH, Bayles TB, Favour CB. The response of serum gamma globulin level and complement titer to adrenocorticotropic hormone therapy in lupus erythematosus disseminatus. J Lab Clin Med 1951; 37(5): 698-702.
[PMID: 14841412]
[44]
Dhir V, Singh AP, Aggarwal A, Naik S, Misra R. Increased T-lymphocyte apoptosis in lupus correlates with disease activity and may be responsible for reduced T-cell frequency: A cross-sectional and longitudinal study. Lupus 2009; 18(9): 785-91.
[http://dx.doi.org/10.1177/0961203309103152] [PMID: 19578102]
[45]
Li M, Yu D, Wang Y, Luo N, Han G, Yang B. Interferon-α activates interleukin-1 receptor-associated kinase 1 to induce regulatory T-cell apoptosis in patients with systemic lupus erythematosus. J Dermatol 2021; 48(8): 1172-85.
[http://dx.doi.org/10.1111/1346-8138.15899] [PMID: 33882150]
[46]
Kim WU, Min SY, Hwang SH, Yoo SA, Kim KJ, Cho CS. Effect of oestrogen on T cell apoptosis in patients with systemic lupus erythematosus. Clin Exp Immunol 2010; 161(3): 453-8.
[http://dx.doi.org/10.1111/j.1365-2249.2010.04194.x] [PMID: 20529085]
[47]
Xue C, Lan-Lan W, Bei C, Jie C, Wei-Hua F. Abnormal Fas/FasL and caspase-3-mediated apoptotic signaling pathways of T lymphocyte subset in patients with systemic lupus erythematosus. Cell Immunol 2006; 239(2): 121-8.
[http://dx.doi.org/10.1016/j.cellimm.2006.05.003] [PMID: 16808908]
[48]
Budd RC, Scharer CD, Barrantes-Reynolds R, et al. T cell homeostatic proliferation promotes a redox state that drives metabolic and epigenetic upregulation of inflammatory pathways in lupus. Antioxid Redox Signal 2022; 36(7-9): 410-22.
[http://dx.doi.org/10.1089/ars.2021.0078] [PMID: 34328790]
[49]
Xie J, Li B, Yao B, et al. Transforming growth factor-β1-regulated Fas/FasL pathway activation suppresses nucleus pulposus cell apoptosis in an inflammatory environment. Biosci Rep 2020; 40(2): BSR20191726.
[http://dx.doi.org/10.1042/BSR20191726] [PMID: 31808511]
[50]
Sun Z, Su Z, Zhou Z, et al. RNA demethylase ALKBH5 inhibits TGF-β-induced EMT by regulating TGF-β/SMAD signaling in non-small cell lung cancer. FASEB J 2022; 36(5): e22283.
[http://dx.doi.org/10.1096/fj.202200005RR] [PMID: 35344216]
[51]
Li WQ, Jiang Q, Aleem E, Kaldis P, Khaled AR, Durum SK. IL-7 promotes T cell proliferation through destabilization of p27Kip1. J Exp Med 2006; 203(3): 573-82.
[http://dx.doi.org/10.1084/jem.20051520] [PMID: 16492801]

Rights & Permissions Print Cite
Article Metrics
27
1
© 2024 Bentham Science Publishers | Privacy Policy