MicroRNA‑155 modulation of CD8<sup>+</sup> T‑cell activity personalizes response to disease‑modifying therapies of patients with relapsing‑remitting multiple sclerosis

Elkhodiry,Aya A.; Zamzam,Dina A.; El Tayebi,Hend M.

doi:10.3892/mi.2023.80

MicroRNA‑155 modulation of CD8⁺ T‑cell activity personalizes response to disease‑modifying therapies of patients with relapsing‑remitting multiple sclerosis

Authors:
- Aya A. Elkhodiry
- Dina A. Zamzam
- Hend M. El Tayebi
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Affiliations: Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt, Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
Published online on: March 20, 2023 https://doi.org/10.3892/mi.2023.80
Article Number: 20
Copyright: © Elkhodiry et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease where activated immune cells can attack oligodendrocytes causing damage to the myelin sheath. Several molecular mechanisms are responsible for the auto‑activation of immune cells such as RNA interference (RNAi) through microRNAs (miRNAs or miRs). In the present study, the role of miR‑155 in regulating CD8⁺ T‑cell activity in patients with relapsing‑remitting multiple sclerosis (RRMS) was investigated, in terms of its migratory functions with regard to intracellular adhesion molecule‑1 (ICAM1) and integrin subunit β2 (ITGB2), and its cytotoxic proteins, perforin and granzyme B. Gene expression of miR‑155, ICAM1, ITGB2, perforin and granzyme B was evaluated following epigenetic modulations using reverse transcription‑quantitative polymerase chain reaction in CD8⁺ T-cells isolated from blood samples of patients with RRMS and compared to healthy controls. The ectopic expression of miR‑155 resulted in a persistent downregulation in all genes of interest related to CD8⁺ T‑cell activation that were positively correlated with the Expanded Disability Status Scale of patients. The present study revealed the interplay between miR‑155, ICAM1, and ITGB2, shedding light on their beneficial use as possible therapeutic regulators and diagnostic biomarkers of disease. Moreover, epigenetic modulations enhancing the efficacy of disease‑modifying therapies (DMTs) may be employed as personalized therapy, to decrease the side effects of DMTs and improve the outcomes of patients.

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1	Bishop M and Rumrill PD: Multiple sclerosis: Etiology, symptoms, incidence and prevalence, and implications for community living and employment. Work. 52:725–734. 2015.PubMed/NCBI View Article : Google Scholar
2	Kamm CP, Uitdehaag BM and Polman CH: Multiple sclerosis: Current knowledge and future outlook. Eur Neurol. 72:132–141. 2014.PubMed/NCBI View Article : Google Scholar
3	Zakaria M, Sharawy M and Anan I: Economic burden of multiple sclerosis in Egypt: A societal perspective. Mult Scler Relat Disord. 37(101563)2020.
4	Ghasemi N, Razavi S and Nikzad E: Multiple sclerosis: Pathogenesis, symptoms, diagnoses and cell-based therapy. Cell J. 19:1–10. 2017.PubMed/NCBI View Article : Google Scholar
5	Hauser SL, Bhan AK, Gilles F, Kemp M, Kerr C and Weiner HL: Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann Neurol. 19:578–587. 1986.PubMed/NCBI View Article : Google Scholar
6	Shi L, Yang X, Froelich CJ and Greenberg AH: Purification and use of granzyme B. Methods Enzymol. 322:125–143. 2000.PubMed/NCBI View Article : Google Scholar
7	Osińska I, Popko K and Demkow U: Perforin: An important player in immune response. Cent Eur J Immunol. 39:109–115. 2014.PubMed/NCBI View Article : Google Scholar
8	Alexander JS, Zivadinov R, Maghzi AH, Ganta VC, Harris MK and Minagar A: Multiple sclerosis and cerebral endothelial dysfunction: Mechanisms. Pathophysiology. 18:3–12. 2011.PubMed/NCBI View Article : Google Scholar
9	Bascones-Martinez A, Mattila R, Gomez-Font R and Meurman JH: Immunomodulatory drugs: Oral and systemic adverse effects. Med Oral Patol Oral Cir Bucal. 19:e24–e31. 2014.PubMed/NCBI View Article : Google Scholar
10	Critchfield JM, Racke MK, Zúñiga-Pflücker JC, Cannella B, Raine CS, Goverman J and Lenardo MJ: T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science. 263:1139–1143. 1994.PubMed/NCBI View Article : Google Scholar
11	Ding SW, Li H, Lu R, Li F and Li WX: RNA silencing: A conserved antiviral immunity of plants and animals. Virus Res. 102:109–115. 2004.PubMed/NCBI View Article : Google Scholar
12	Paraboschi EM, Soldà G, Gemmati D, Orioli E, Zeri G, Benedetti MD, Salviati A, Barizzone N, Leone M, Duga S and Asselta R: Genetic association and altered gene expression of mir-155 in multiple sclerosis patients. Int J Mol Sci. 12:8695–8712. 2011.PubMed/NCBI View Article : Google Scholar
13	Ma X, Zhou J, Zhong Y, Jiang L, Mu P, Li Y, Singh N, Nagarkatti M and Nagarkatti P: Expression, regulation and function of microRNAs in multiple sclerosis. Int J Med Sci. 11:810–818. 2014.PubMed/NCBI View Article : Google Scholar
14	Junker A, Krumbholz M, Eisele S, Mohan H, Augstein F, Bittner R, Lassmann H, Wekerle H, Hohlfeld R and Meinl E: MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain. 132:3342–3352. 2009.PubMed/NCBI View Article : Google Scholar
15	Seddiki N, Brezar V, Ruffin N, Lévy Y and Swaminathan S: Role of miR-155 in the regulation of lymphocyte immune function and disease. Immunology. 142:32–38. 2014.PubMed/NCBI View Article : Google Scholar
16	Niwald M, Migdalska-Sęk M, Brzeziańska-Lasota E and Miller E: Evaluation of selected MicroRNAs expression in remission phase of multiple sclerosis and their potential link to cognition, depression, and disability. J Mol Neurosci. 63:275–282. 2017.PubMed/NCBI View Article : Google Scholar
17	Baulina N, Kulakova O, Kiselev I, Osmak G, Popova E, Boyko A and Favorova O: Immune-related miRNA expression patterns in peripheral blood mononuclear cells differ in multiple sclerosis relapse and remission. J Neuroimmunol. 317:67–76. 2018.PubMed/NCBI View Article : Google Scholar
18	Song J and Lee JE: miR-155 is involved in Alzheimer's disease by regulating T lymphocyte function. Front Aging Neurosci. 7(61)2015.PubMed/NCBI View Article : Google Scholar
19	Tsai CY, Allie SR, Zhang W and Usherwood EJ: MicroRNA miR-155 affects antiviral effector and effector Memory CD8 T cell differentiation. J Virol. 87:2348–2351. 2013.PubMed/NCBI View Article : Google Scholar
20	Elkhodiry AA, Zamzam DA and El Tayebi HM: miR-155 and functional proteins of CD8+ T cells as potential prognostic biomarkers for relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 53(103078)2021.PubMed/NCBI View Article : Google Scholar
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
22	Yusuf-Makagiansar H, Anderson ME, Yakovleva TV, Murray JS and Siahaan TJ: Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases. Med Res Rev. 22:146–167. 2002.PubMed/NCBI View Article : Google Scholar
23	Yang X, Wu Y, Zhang B and Ni B: Noncoding RNAs in multiple sclerosis. Clin Epigenetics. 10(149)2018.PubMed/NCBI View Article : Google Scholar
24	Lukiw WJ, Surjyadipta B, Dua P and Alexandrov PN: Common micro RNAs (miRNAs) target complement factor H (CFH) regulation in Alzheimer's disease (AD) and in age-related macular degeneration (AMD). Int J Biochem Mol Biol. 3:105–116. 2012.PubMed/NCBI
25	El Tayebi HM, Waly AA, Assal RA, Hosny KA, Esmat G and Abdelaziz AI: Transcriptional activation of the IGF-II/IGF-1R axis and inhibition of IGFBP-3 by miR-155 in hepatocellular carcinoma. Oncol Lett. 10:3206–3212. 2015.PubMed/NCBI View Article : Google Scholar
26	Atwa S, Hosny K, Handoussa H and El Tayebi H: Paradoxically functioning onco-miR-155 and the tumor suppressor miR-194 consensus on PD-L1 immune checkpoint upregulation via MALAT-1 and XIST in hepatocellular carcinoma. J Hepatol. 68 (Suppl 1):S610–S611. 2018.
27	Junker A: Pathophysiology of translational regulation by microRNAs in multiple sclerosis. FEBS Lett. 585:3738–3746. 2011.PubMed/NCBI View Article : Google Scholar
28	Reyes-Long S, Cortes-Altamirano JL, Clavijio-Cornejo D, Gutiérrez M, Bertolazzi C, Bandala C, Pineda C and Alfaro-Rodríguez A: Nociceptive related microRNAs and their role in rheumatoid arthritis. Mol Biol Rep. 47:7265–7272. 2020.PubMed/NCBI View Article : Google Scholar
29	Leng RX, Pan HF, Qin WZ, Chen GM and Ye DQ: Role of microRNA-155 in autoimmunity. Cytokine Growth Factor Rev. 22:141–147. 2011.PubMed/NCBI View Article : Google Scholar
30	Azzaoui K, Blommers M, Götte M, Zimmermann K, Liu H and Fretz H: Discovery of small molecule drugs targeting the biogenesis of microRNA-155 for the treatment of systemic lupus erythematosus. Chimia (Aarau). 74:798–802. 2020.PubMed/NCBI View Article : Google Scholar
31	Kamphuis WW, Troletti C, Reijerkerk A, Romero IA and de Vries HE: The blood-brain barrier in multiple sclerosis: microRNAs as key regulators. CNS Neurol Disord Drug Targets. 14:157–167. 2015.PubMed/NCBI View Article : Google Scholar
32	Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M, et al: A mammalian microRNA expression atlas based on small RNA library sequencing. Cell. 129:1401–1414. 2007.PubMed/NCBI View Article : Google Scholar
33	Wu H, Neilson JR, Kumar P, Manocha M, Shankar P, Sharp PA and Manjunath N: miRNA profiling of naïve, effector and memory CD8 T cells. PLoS One. 2(e1020)2007.PubMed/NCBI View Article : Google Scholar
34	Neilson JR, Zheng GXY, Burge CB and Sharp PA: Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev. 21:578–589. 2007.PubMed/NCBI View Article : Google Scholar
35	Elovaara I, Ukkonen M, Leppäkynnäs M, Lehtimäki T, Luomala M, Peltola J and Dastidar P: Adhesion molecules in multiple sclerosis: Relation to subtypes of disease and methylprednisolone therapy. Arch Neurol. 57:546–551. 2000.PubMed/NCBI View Article : Google Scholar
36	Fujii C, Kondo T, Ochi H, Okada Y, Hashi Y, Adachi T, Shin-Ya M, Matsumoto S, Takahashi R, Nakagawa M and Mizuno T: Altered T cell phenotypes associated with clinical relapse of multiple sclerosis patients receiving fingolimod therapy. Sci Rep. 6(35314)2016.PubMed/NCBI View Article : Google Scholar
37	Cerutti C, Soblechero-Martin P, Wu D, Lopez-Ramirez MA, de Vries H, Sharrack B, Male DK and Romero IA: MicroRNA-155 contributes to shear-resistant leukocyte adhesion to human brain endothelium in vitro. Fluids Barriers CNS. 13(8)2016.PubMed/NCBI View Article : Google Scholar
38	Lind EF, Elford AR and Ohashi PS: Micro-RNA 155 is required for optimal CD8+ T cell responses to acute viral and intracellular bacterial challenges. J Immunol. 190:1210–1216. 2013.PubMed/NCBI View Article : Google Scholar
39	Blüml S, Bonelli M, Niederreiter B, Puchner A, Mayr G, Hayer S, Koenders MI, van den Berg WB, Smolen J and Redlich K: Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum. 63:1281–1288. 2011.PubMed/NCBI View Article : Google Scholar
40	Lashine YA, Salah S, Aboelenein HR and Abdelaziz AI: Correcting the expression of miRNA-155 represses PP2Ac and enhances the release of IL-2 in PBMCs of juvenile SLE patients. Lupus. 24:240–247. 2015.PubMed/NCBI View Article : Google Scholar
41	Yasuda M, Tanaka Y, Tamura M, Fujii K, Sugaya M, So T, Takenoyama M and Yasumoto K: Stimulation of beta1 integrin down-regulates ICAM-1 expression and ICAM-1-dependent adhesion of lung cancer cells through focal adhesion kinase. Cancer Res. 61:2022–2030. 2001.PubMed/NCBI
42	Scholer A, Hugues S, Boissonnas A, Fetler L and Amigorena S: Intercellular adhesion molecule-1-dependent stable interactions between T cells and dendritic cells determine CD8+ T cell memory. Immunity. 28:258–270. 2008.PubMed/NCBI View Article : Google Scholar
43	Bullard DC, Hu X, Schoeb TR, Collins RG, Beaudet AL and Barnum SR: Intercellular adhesion molecule-1 expression is required on multiple cell types for the development of experimental autoimmune encephalomyelitis. J Immunol. 178:851–857. 2007.PubMed/NCBI View Article : Google Scholar
44	Bullard DC, Hu X, Schoeb TR, Axtell RC, Raman C and Barnum SR: Critical requirement of CD11b (Mac-1) on T cells and accessory cells for development of experimental autoimmune encephalomyelitis. J Immunol. 175:6327–6333. 2005.PubMed/NCBI View Article : Google Scholar
45	Faraoni I, Antonetti FR, Cardone J and Bonmassar E: miR-155 gene: A typical multifunctional microRNA. Biochim Biophys Acta. 1792:497–505. 2009.PubMed/NCBI View Article : Google Scholar