Abstract
Increasing evidence has shown that miRNA-451a (miR-451a) is associated with the development of systemic lupus erythematosus (SLE); however, the mechanism of this association is not fully known. The present study found an increased expression of miR-451a in the spleen and thymus of an SLE mice model. A decrease in miR-451a expression partly relieved the enlargement of the spleen and decreased the proteinuria content and immune complex deposits. The deficiency in miR-451a also decreased numbers of CD4+CD69+ and CD4+/CD8+ T cells and the levels of the serum cytokines IL-17a and IL-4. The IFN regulatory factor (IRF) 8 was highly expressed in the immune organs of wild-type mice but was suppressed in SLE-like mice. A dual-luciferase reporter assay was carried out in combination with gene silencing and overexpression to verify that IRF8 was a target of miR-451a in vitro and in vivo. The data indicate the function and a target of miR-451a in SLE, providing a new target for SLE therapy.
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Abbreviations
- CBB:
-
Coomassie brilliant blue
- ELISA:
-
Enzyme-linked immunosorbent assay
- IRF8:
-
IFN regulatory factor 8
- miR-451a:
-
miRNA-451a
- SLE:
-
Systemic lupus erythematosus
- Tfh:
-
T-follicular helper
References
Wahren-Herlenius, M., and T. Dorner. 2013. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 382(9894): 819–831.
Bengtsson, A.A. and Ronnblom, L. 2016. Systemic lupus erythematosus: still a challenge for physicians. J Intern Med
Mok, C.C., R.C. Kwok, and P.S. Yip. 2013. Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis Rheum 65(8): 2154–2160.
Anaya, J.M., C. Canas, R.D. Mantilla, R. Pineda-Tamayo, G.J. Tobon, C. Herrera-Diaz, D.M. Rendon, A. Rojas-Villarraga, and M. Uribe. 2011. Lupus nephritis in Colombians: contrasts and comparisons with other populations. Clin Rev Allergy Immunol 40(3): 199–207.
Taher, T.E., H.A. Muhammad, E. Bariller, F. Flores-Borja, Y. Renaudineau, D.A. Isenberg, and R.A. Mageed. 2013. B-lymphocyte signalling abnormalities and lupus immunopathology. Int Rev Immunol 32(4): 428–444.
Moulton, V.R., and G.C. Tsokos. 2015. T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J Clin Invest 125(6): 2220–2227.
Asano, S., K. Mori, K. Yamazaki, T. Sata, A. Kurata, Y. Sato, H. Odajima, Y. Akaike, H. Wakasa, and M. Kojima. 2014. Necrotizing lymphadenitis (NEL) is a systemic disease characterized by blastic transformation of CD8+ cells and apoptosis of CD4+ cells. Virchows Arch 464(1): 95–103.
Talaat, R.M., S.F. Mohamed, I.H. Bassyouni, and A.A. Raouf. 2015. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: correlation with disease activity. Cytokine 72(2): 146–153.
Schoenfeld, S.R., S. Kasturi, and K.H. Costenbader. 2013. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review. Semin Arthritis Rheum 43(1): 77–95.
Mancino, A., and G. Natoli. 2016. Specificity and Function of IRF Family Transcription Factors: Insights from Genomics. J Interferon Cytokine Res 36(7): 462–469.
Yanez, A., and H.S. Goodridge. 2016. Interferon regulatory factor 8 and the regulation of neutrophil, monocyte, and dendritic cell production. Curr Opin Hematol 23(1): 11–17.
Abrams, S.I., C.S. Netherby, D.Y. Twum, and M.N. Messmer. 2016. Relevance of Interferon Regulatory Factor-8 Expression in Myeloid-Tumor Interactions. J Interferon Cytokine Res 36(7): 442–453.
Wang, H., and H.C. Morse 3rd. 2009. IRF8 regulates myeloid and B lymphoid lineage diversification. Immunol Res 43(1-3): 109–117.
Salloum, R., and T.B. Niewold. 2011. Interferon regulatory factors in human lupus pathogenesis. Transl Res 157(6): 326–331.
Ambros, V. 2004. The functions of animal microRNAs. Nature 431(7006): 350–355.
Kloosterman, W.P., and R.H. Plasterk. 2006. The diverse functions of microRNAs in animal development and disease. Dev Cell 11(4): 441–450.
Singh, R.P., I. Massachi, S. Manickavel, S. Singh, N.P. Rao, S. Hasan, D.K. Mc Curdy, S. Sharma, D. Wong, B.H. Hahn, and H. Rehimi. 2013. The role of miRNA in inflammation and autoimmunity. Autoimmun Rev 12(12): 1160–1165.
Qu, B., and N. Shen. 2015. miRNAs in the Pathogenesis of Systemic Lupus Erythematosus. Int J Mol Sci 16(5): 9557–9572.
Su, Z., L. Ni, W. Yu, Z. Yu, D. Chen, E. Zhang, Y. Li, Y. Wang, X. Li, S. Yang, Y. Gui, Y. Lai, and J. Ye. 2015. MicroRNA-451a is associated with cell proliferation, migration and apoptosis in renal cell carcinoma. Mol Med Rep 11(3): 2248–2254.
Chen, Q., H. Hu, D. Jiao, J. Yan, W. Xu, X. Tang, J. Chen, and J. Wang. 2016. miR-126-3p and miR-451a correlate with clinicopathological features of lung adenocarcinoma: The underlying molecular mechanisms. Oncol Rep 36(2): 909–917.
Gorur, A., S. Balci Fidanci, N. Dogruer Unal, L. Ayaz, S. Akbayir, H. Yildirim Yaroglu, M. Dirlik, M.S. Serin, and L. Tamer. 2013. Determination of plasma microRNA for early detection of gastric cancer. Mol Biol Rep 40(3): 2091–2096.
Baulina, N.M., O.G. Kulakova, and O.O. Favorova. 2016. MicroRNAs: The Role in Autoimmune Inflammation. Acta Naturae 8(1): 21–33.
Xu, L.B., N. Chi, and W. Shi. 2015. Amiloride, a urokinase-type plasminogen activator receptor (uTPA) inhibitor, reduces proteinurea in podocytes. Gen Mol Res 14(3): 9518–9529.
Olin, A.I., M. Morgelin, L. Truedsson, G. Sturfelt, and A.A. Bengtsson. 2014. Pathogenic mechanisms in lupus nephritis: Nucleosomes bind aberrant laminin beta1 with high affinity and colocalize in the electron-dense deposits. Arthritis Rheumatol 66(2): 397–406.
Deenick, E.K., A. Chan, C.S. Ma, D. Gatto, P.L. Schwartzberg, R. Brink, and S.G. Tangye. 2010. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33(2): 241–253.
Bubier, J.A., T.J. Sproule, O. Foreman, R. Spolski, D.J. Shaffer, H.C. Morse 3rd, W.J. Leonard, and D.C. Roopenian. 2009. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci U S A 106(5): 1518–1523.
Simpson, N., P.A. Gatenby, A. Wilson, S. Malik, D.A. Fulcher, S.G. Tangye, H. Manku, T.J. Vyse, G. Roncador, G.A. Huttley, C.C. Goodnow, C.G. Vinuesa, and M.C. Cook. 2010. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum 62(1): 234–244.
Mak, A., and N.Y. Kow. 2014. The pathology of T cells in systemic lupus erythematosus. J Immunol Res 2014: 419029.
Martin, J.C., D.L. Baeten, and R. Josien. 2014. Emerging role of IL-17 and Th17 cells in systemic lupus erythematosus. Clin Immunol 154(1): 1–12.
Panda, A.K. and Das, B.K. 2016. Diminished IL-17A levels may protect filarial-infected individuals from development of rheumatoid arthritis and systemic lupus erythematosus. Lupus
Ohl, K., and K. Tenbrock. 2011. Inflammatory cytokines in systemic lupus erythematosus. J Biomed Biotechnol 2011: 432595.
Li, D., B. Guo, H. Wu, L. Tan, C. Chang, and Q. Lu. 2015. Interleukin-17 in systemic lupus erythematosus: a comprehensive review. Autoimmunity 48(6): 353–361.
Wong, C.K., C.Y. Ho, E.K. Li, and C.W. Lam. 2000. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 9(8): 589–593.
Luo, S., Y. Wang, M. Zhao, and Q. Lu. 2016. The important roles of type I interferon and interferon-inducible genes in systemic lupus erythematosus. Int Immunopharmacol 40: 542–549.
Lazzari, E., and C.A. Jefferies. 2014. IRF5-mediated signaling and implications for SLE. Clin Immunol 153(2): 343–352.
Graham, R.R., S.V. Kozyrev, E.C. Baechler, M.V. Reddy, R.M. Plenge, J.W. Bauer, W.A. Ortmann, T. Koeuth, M.F. Gonzalez Escribano, B. Pons-Estel, M. Petri, M. Daly, P.K. Gregersen, J. Martin, D. Altshuler, T.W. Behrens, and M.E. Alarcon-Riquelme. 2006. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 38(5): 550–555.
Lessard, C.J., I. Adrianto, J.A. Ice, G.B. Wiley, J.A. Kelly, S.B. Glenn, A.J. Adler, H. Li, A. Rasmussen, A.H. Williams, J. Ziegler, M.E. Comeau, M. Marion, B.E. Wakeland, C. Liang, P.S. Ramos, K.M. Grundahl, C.J. Gallant, M.E. Alarcon-Riquelme, G.S. Alarcon, J.M. Anaya, S.C. Bae, S.A. Boackle, E.E. Brown, D.M. Chang, S.K. Cho, L.A. Criswell, J.C. Edberg, B.I. Freedman, G.S. Gilkeson, C.O. Jacob, J.A. James, D.L. Kamen, R.P. Kimberly, J.H. Kim, J. Martin, J.T. Merrill, T.B. Niewold, S.Y. Park, M.A. Petri, B.A. Pons-Estel, R. Ramsey-Goldman, J.D. Reveille, R.H. Scofield, Y.W. Song, A.M. Stevens, B.P. Tsao, L.M. Vila, T.J. Vyse, C.Y. Yu, J.M. Guthridge, K.M. Kaufman, J.B. Harley, E.K. Wakeland, C.D. Langefeld, P.M. Gaffney, C.G. Montgomery, and K.L. Moser. 2012. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am J Hum Genet 90(4): 648–660.
Ruiz-Larranaga, O., P. Migliorini, M. Uribarri, L. Czirjak, M.C. Alcaro, J. Del Amo, M. Iriondo, C. Manzano, S. Escorza-Trevino, and A. Estonba. 2016. Genetic association study of systemic lupus erythematosus and disease subphenotypes in European populations. Clin Rheumatol 35(5): 1161–1168.
Li, S.W., Y. He, Z.H. Zheng, D.W. Liu, and Z.S. Liu. 2014. Single-nucleotide polymorphisms of IRF8 gene are associated with systemic lupus erythematosus in Chinese Han population. Int J Immunogenet 41(2): 112–118.
Shin, D.M., C.H. Lee, and H.C. Morse 3rd. 2011. IRF8 governs expression of genes involved in innate and adaptive immunity in human and mouse germinal center B cells. PLoS ONE 6(11), e27384.
Sjostrand, M., A. Johansson, L. Aqrawi, T. Olsson, M. Wahren-Herlenius, and A. Espinosa. 2016. The Expression of BAFF Is Controlled by IRF Transcription Factors. J Immunol 196(1): 91–96.
Pan, X., R. Wang, and Z.X. Wang. 2013. The potential role of miR-451 in cancer diagnosis, prognosis, and therapy. Mol Cancer Ther 12(7): 1153–1162.
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Cheng, J., Wu, R., Long, L. et al. miRNA-451a Targets IFN Regulatory Factor 8 for the Progression of Systemic Lupus Erythematosus. Inflammation 40, 676–687 (2017). https://doi.org/10.1007/s10753-017-0514-8
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DOI: https://doi.org/10.1007/s10753-017-0514-8