Startseite Lebenswissenschaften MiR-23a-3p-regulated abnormal acetylation of FOXP3 induces regulatory T cell function defect in Graves’ disease
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MiR-23a-3p-regulated abnormal acetylation of FOXP3 induces regulatory T cell function defect in Graves’ disease

  • Danhua Zhang , Xinguang Qiu , Jianhua Li , Shouhua Zheng , Liwen Li und Hongchao Zhao EMAIL logo
Veröffentlicht/Copyright: 3. Dezember 2018
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 400 Heft 5

Abstract

This study aims to investigate the mechanism of miR-23a-3p in regulating Treg dysfunction in Graves’ disease (GD). The percentage of Treg cells and interleukin (IL)-17+ T cells were determined by flow cytometry. The expression of forkhead box P3 (FOXP3), sirtuin 1 (SIRT1), RAR-related orphan receptor gamma t (RORγt) and miR-23a-3p was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blot. CD4+ T cells were treated with SIRT1 specific inhibitor EX-527 or left untreated. MiR-23a-3p mimic or inhibitor were transfected into CD4+ T cells. Acetylation expression of FOXP3 was analyzed by immunoprecipitation. The suppressive function of Treg was analyzed by the carboxyfluorescein succinimidyl ester (CFSE) assay. The results showed that GD patients have significantly less Treg cells and more IL-17+ T cells. FOXP3 and miR-23a-3p were significantly down-regulated meanwhile SIRT1 and RORγt were up-regulated in GD patients. FOXP3 acetylation level of the GD group was lower than that of control groups. After EX-527 treatment, the percentage of Treg cells, expression and acetylation level of FOXP3 were significantly increased in the GD group. GD Tregs exhibited weaker suppressive activity, miR-23a-3p mimic suppressed SIRT1 expression and suppressive-activity of Tregs whereas it promoted the expression and acetylation level of FOXP3 in the GD group. Our findings suggest that the Treg function defect in GD patients is mediated by the abnormal acetylation of FOXP3, which is regulated by miR-23a-3p via targeting SIRT1.

Keywords: FOXP3 acetylation; Graves’ disease (GD); miR-23a-3p; Treg function defect

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 31602600

Funding statement: This study was supported by grants from National Natural Science Foundation of China (NSFC, Grant No. 31602600).

References

Akimova, T., Xiao, H., Liu, Y., Bhatti, T.R., Jiao, J., Eruslanov, E., Singhal, S., Wang, L., Han, R., Zacharia, K., et al. (2014). Targeting sirtuin-1 alleviates experimental autoimmune colitis by induction of Foxp3+ T-regulatory cells. Mucosal Immunol. 7, 1209–1220.10.1038/mi.2014.10Suche in Google Scholar PubMed PubMed Central

Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S.E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., et al. (2006). Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J. Clin. Invest. 116, 1713–1722.10.1172/JCI25112Suche in Google Scholar PubMed PubMed Central

Beier, U.H., Wang, L., Bhatti, T.R., Liu, Y., Han, R., Ge, G., and Hancock, W.W. (2011). Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol. Cell. Biol. 31, 1022–1029.10.1128/MCB.01206-10Suche in Google Scholar PubMed PubMed Central

Beier, U.H., Wang, L., Han, R., Akimova, T., Liu, Y., and Hancock, W.W. (2012). Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci Signal. 5, ra45.10.1126/scisignal.2002873Suche in Google Scholar PubMed PubMed Central

Chen, H.P., Zhao, Y.T., and Zhao, T.C. (2015). Histone deacetylases and mechanisms of regulation of gene expression. Crit Rev Oncog. 20, 35–47.10.1615/CritRevOncog.2015012997Suche in Google Scholar PubMed PubMed Central

Cooper, G.S. and Stroehla, B.C. (2003). The epidemiology of autoimmune diseases. Autoimmun Rev. 2, 119–125.10.1016/S1568-9972(03)00006-5Suche in Google Scholar PubMed

Dieker, J. and Muller, S. (2010). Epigenetic histone code and autoimmunity. Clin. Rev. Allergy Immunol. 39, 78–84.10.1007/s12016-009-8173-7Suche in Google Scholar PubMed

Ellis, J.S., Wan, X., and Braley-Mullen, H. (2013). Transient depletion of CD4+ CD25+ regulatory T cells results in multiple autoimmune diseases in wild-type and B-cell-deficient NOD mice. Immunology 139, 179–186.10.1111/imm.12065Suche in Google Scholar PubMed PubMed Central

Fontenot, J.D., Gavin, M.A., and Rudensky, A.Y. (2003). Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat. Immunol. 4, 330–336.10.1038/ni904Suche in Google Scholar PubMed

Hiratsuka, I., Yamada, H., Munetsuna, E., Hashimoto, S., and Itoh, M. (2016). Circulating microRNAs in Graves’ disease in relation to clinical activity. Thyroid 26, 1431–1440.10.1089/thy.2016.0062Suche in Google Scholar PubMed

Levine, M.H., Wang, Z., Xiao, H., Jiao, J., Wang, L., Bhatti, T.R., Hancock, W.W., and Beier, U.H. (2016). Targeting Sirtuin-1 prolongs murine renal allograft survival and function. Kidney Int. 89, 1016–1026.10.1016/j.kint.2015.12.051Suche in Google Scholar PubMed PubMed Central

Li, C., Yuan, J., Zhu, Y.F., Yang, X.J., Wang, Q., Xu, J., He, S.T., and Zhang, J.A. (2016). Imbalance of Th17/Treg in different subtypes of autoimmune thyroid diseases. Cell Physiol. Biochem. 40, 245–252.10.1159/000452541Suche in Google Scholar PubMed

O’Connell, R.M., Rao, D.S., Chaudhuri, A.A., and Baltimore, D. (2010). Physiological and pathological roles for microRNAs in the immune system. Nat. Rev. Immunol. 10, 111–122.10.1038/nri2708Suche in Google Scholar PubMed

Pawlowski, P., Grubczak, K., Kostecki, J., Ilendo-Poskrobko, E., Moniuszko, M., Pawlowska, M., Rejdak, R., Reszec, J., and Mysliwiec, J. (2017). Decreased frequencies of peripheral blood CD4+ CD25+ CD127- Foxp3+ in patients with Graves’ disease and Graves’ orbitopathy: enhancing effect of insulin growth factor-1 on Treg cells. Horm. Metab. Res. 49, 185–191.10.1055/s-0042-122780Suche in Google Scholar PubMed

Qin, J., Zhou, J., Fan, C., Zhao, N., Liu, Y., Wang, S., Cui, X., Huang, M., Guan, H., and Li, Y. (2017). Increased circulating Th17 but decreased CD4+ Foxp3+ Treg and CD19+ CD1dhi CD5+ Breg subsets in new-onset Graves’ disease. Biomed Res. Int. 2017, 8431838.10.1155/2017/8431838Suche in Google Scholar PubMed PubMed Central

Rydzewska, M., Jaromin, M., Pasierowska, I.E., Stozek, K., and Bossowski, A. (2018). Role of the T and B lymphocytes in pathogenesis of autoimmune thyroid diseases. Thyroid Res. 11, 2.10.1186/s13044-018-0046-9Suche in Google Scholar PubMed PubMed Central

Sarumaru, M., Watanabe, M., Inoue, N., Hisamoto, Y., Morita, E., Arakawa, Y., Hidaka, Y., and Iwatani, Y. (2016). Association between functional SIRT1 polymorphisms and the clinical characteristics of patients with autoimmune thyroid disease. Autoimmunity 49, 329–337.10.3109/08916934.2015.1134506Suche in Google Scholar PubMed

Sauve, A.A., Wolberger, C., Schramm, V.L., and Boeke, J.D. (2006). The biochemistry of sirtuins. Annu. Rev. Biochem. 75, 435–465.10.1146/annurev.biochem.74.082803.133500Suche in Google Scholar PubMed

Tessarz, P. and Kouzarides, T. (2014). Histone core modifications regulating nucleosome structure and dynamics. Nat. Rev. Mol. Cell Biol. 15, 703–708.10.1038/nrm3890Suche in Google Scholar PubMed

Yang, X., Lun, Y., Jiang, H., Liu, X., Duan, Z., Xin, S., and Zhang, J. (2018). SIRT1-regulated abnormal acetylation of FOXP3 induces regulatory T-cell function defect in Hashimoto’s thyroiditis. Thyroid 28, 246–256.10.1089/thy.2017.0286Suche in Google Scholar PubMed

Yu, J. and Auwerx, J. (2010). Protein deacetylation by SIRT1: an emerging key post-translational modification in metabolic regulation. Pharmacol. Res. 62, 35–41.10.1016/j.phrs.2009.12.006Suche in Google Scholar PubMed PubMed Central

Zeng, C., Shi, X., Zhang, B., Liu, H., Zhang, L., Ding, W., and Zhao, Y. (2012). The imbalance of Th17/Th1/Tregs in patients with type 2 diabetes: relationship with metabolic factors and complications. J. Mol. Med. (Berl.) 90, 175–186.10.1007/s00109-011-0816-5Suche in Google Scholar PubMed

Zheng, L., Zhuang, C., Wang, X., and Ming, L. (2018). Serum miR-146a, miR-155, and miR-210 as potential markers of Graves’ disease. J. Clin. Lab. Anal. 32, e22266.10.1002/jcla.22266Suche in Google Scholar PubMed PubMed Central

Received: 2018-08-12
Accepted: 2018-10-26
Published Online: 2018-12-03
Published in Print: 2019-05-27

©2019 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/hsz-2018-0343
Schlagwörter für diesen Artikel
FOXP3 acetylation; Graves’ disease (GD); miR-23a-3p; Treg function defect

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Complexity of type IV collagens: from network assembly to function
  4. Structural and mechanistic aspects of S-S bonds in the thioredoxin-like family of proteins
  5. Oxidative stress and antioxidants in the pathophysiology of malignant melanoma
  6. Research Articles/Short Communications
  7. Genes and Nucleic Acids
  8. Dynamic characteristics of the mitochondrial genome in SCNT pigs
  9. Protein Structure and Function
  10. Conversion of chenodeoxycholic acid to cholic acid by human CYP8B1
  11. Molecular Medicine
  12. The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity
  13. MiR-23a-3p-regulated abnormal acetylation of FOXP3 induces regulatory T cell function defect in Graves’ disease
  14. Cell Biology and Signaling
  15. Evidence for a protective role of the CX3CL1/CX3CR1 axis in a model of amyotrophic lateral sclerosis
  16. LncRNA TINCR/microRNA-107/CD36 regulates cell proliferation and apoptosis in colorectal cancer via PPAR signaling pathway based on bioinformatics analysis
  17. Regulatory effect of hsa-miR-5590-3P on TGFβ signaling through targeting of TGFβ-R1, TGFβ-R2, SMAD3 and SMAD4 transcripts
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