MicroRNA‑21‑5p protects melanocytes via targeting STAT3 and modulating Treg/Teff balance to alleviate vitiligo

Huo,Jing; Liu,Taibin; Li,Fenghua; Song,Xinfeng; Hou,Xiuli

doi:10.3892/mmr.2020.11689

MicroRNA‑21‑5p protects melanocytes via targeting STAT3 and modulating Treg/Teff balance to alleviate vitiligo

Authors:
- Jing Huo
- Taibin Liu
- Fenghua Li
- Xinfeng Song
- Xiuli Hou
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Affiliations: Department of Dermatology, Dezhou People's Hospital, Dezhou, Shandong 253014, P.R. China, Department of Endocrinology, Dezhou People's Hospital, Dezhou, Shandong 253014, P.R. China, Pathology Laboratory, Dezhou College, Dezhou, Shandong 253000, P.R. China
Published online on: November 16, 2020 https://doi.org/10.3892/mmr.2020.11689
Article Number: 51
Copyright: © Huo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Vitiligo (VIT) is caused by loss and degradation of functional epidermal melanocytes. Studies have indicated that melanocyte destruction may be associated with an imbalance between regulatory T cells (Treg cells) and effector T cells (Teff cells). The current study aimed to investigate the molecular mechanism through which Treg/Teff balance affects VIT pathogenesis. To explore this, peripheral blood mononuclear cells were isolated from patients with VIT and healthy individuals. The present study revealed that the proportions of CD4⁺ T cells, Treg cells and T helper 1 (Th1) cells were decreased in patients with VIT, but those of Teff cells (Th17 and Th22 cells) were increased; additionally, Foxp3 expression was decreased, but the expression levels of interferon‑γ, interleukin (IL)‑17A and IL‑22 were increased. Furthermore, in patients with VIT, microRNA (miR)‑21‑5p expression was decreased, while that of STAT3 was increased. Further in vitro experiments in CD4⁺ T cells revealed that STAT3 was targeted by miR‑21‑5p. Functional analysis further indicated that miR‑21‑5p overexpression in Th17‑polarized CD4⁺ T cells decreased the proportion of Teff cells and associated cytokines, such as IL‑17A and IL‑22, but increased the proportion of Treg cells and Foxp3. However, the effects of miR‑21‑5p overexpression were partly reversed by STAT3 overexpression. Increased apoptosis of melanocytes was detected after co‑culture with Th17‑polarized CD4⁺ T cells in the presence of a miR‑21‑5p mimic. However, this indirect effect of the miR‑21‑5p mimic on melanocytes was decreased via STAT3 overexpression. Therefore, miR‑21‑5p may protect melanocytes via targeting STAT3 and regulating Treg/Teff balance. The current findings may provide a possible treatment method for managing VIT.

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1	Ezzedine K, Eleftheriadou V, Whitton M and van Geel N: Vitiligo. Lancet. 386:74–84. 2015. View Article : Google Scholar : PubMed/NCBI
2	Lai YC, Yew YW, Kennedy C and Schwartz RA: Vitiligo and depression: A systematic review and meta-analysis of observational studies. Br J Dermatol. 177:708–718. 2017. View Article : Google Scholar : PubMed/NCBI
3	Xie H, Zhou F, Liu L, Zhu G, Li Q, Li C and Gao T: Vitiligo: How do oxidative stress-induced autoantigens trigger autoimmunity? J Dermatolo Sci. 81:3–9. 2016. View Article : Google Scholar
4	Lv M, Li Z, Liu J, Lin F, Zhang Q, Li Z, Wang Y, Wang K and Xu Y: MicroRNA155 inhibits the proliferation of CD8⁺ T cells via upregulating regulatory T cells in vitiligo. Mol Med Rep. 20:3617–3624. 2019.PubMed/NCBI
5	Lin JY and Fisher DE: Melanocyte biology and skin pigmentation. Nature. 445:843–850. 2007. View Article : Google Scholar : PubMed/NCBI
6	Patel S, Rauf A, Khan H, Meher BR and Hassan SSU: A holistic review on the autoimmune disease vitiligo with emphasis on the causal factors. Biomed Pharmacother. 92:501–508. 2017. View Article : Google Scholar : PubMed/NCBI
7	Frisoli ML and Harris JE: Vitiligo: Mechanistic insights lead to novel treatments. J Allergy Clin Immunol. 140:654–662. 2017. View Article : Google Scholar : PubMed/NCBI
8	Sabat R, Wolk K, Loyal L, Docke WD and Ghoreschi K: T cell pathology in skin inflammation. Semin Immunopathol. 41:359–377. 2019. View Article : Google Scholar : PubMed/NCBI
9	Zhu W, Chen X, Yu J, Xiao Y, Li Y, Wan S, Su W and Liang D: Baicalin modulates the Treg/Teff balance to alleviate uveitis by activating the aryl hydrocarbon receptor. Biochem Pharmacol. 154:18–27. 2018. View Article : Google Scholar : PubMed/NCBI
10	Wang Y, Zhang S, Liang Z, Feng M, Zhao X, Qin K, Gao C, Li X, Guo H and Luo J: Metformin attenuates bleomycin-induced scleroderma by regulating the balance of Treg/Teff cells and reducing spleen germinal center formation. Mol Immunol. 114:72–80. 2019. View Article : Google Scholar : PubMed/NCBI
11	Kalekar LA and Rosenblum MD: Regulatory T cells in inflammatory skin disease: From mice to humans. Int Immunol. 31:457–463. 2019. View Article : Google Scholar : PubMed/NCBI
12	De Santis G, Ferracin M, Biondani A, Caniatti L, Rosaria Tola M, Castellazzi M, Zagatti B, Battistini L, Borsellino G, Fainardi E, et al: Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J Neuroimmunol. 226:165–171. 2010. View Article : Google Scholar : PubMed/NCBI
13	Mansuri MS, Singh M and Begum R: miRNA signatures and transcriptional regulation of their target genes in vitiligo. J Dermatol Sci. 84:50–58. 2016. View Article : Google Scholar : PubMed/NCBI
14	Yan S, Shi J, Sun D and Lyu L: Current insight into the roles of microRNA in vitiligo. Mol Biol Rep. 47:3211–3219. 2020. View Article : Google Scholar : PubMed/NCBI
15	Zheng X, Dong L, Wang K, Zou H, Zhao S, Wang Y and Wang G: MiR-21 participates in the PD-1/PD-L1 pathway-mediated imbalance of Th17/Treg cells in patients after gastric cancer resection. Ann Surg Oncol. 26:884–893. 2019. View Article : Google Scholar : PubMed/NCBI
16	Dong L, Wang X, Tan J, Li H, Qian W, Chen J, Chen Q, Wang J, Xu W, Tao C and Wang S: Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis. J Cell Mol Med. 18:2213–2224. 2014. View Article : Google Scholar : PubMed/NCBI
17	Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothé F, Simion A, Akl H, Mourtada M, El Rifai M, Burny A, et al: Human natural Treg microRNA signature: Role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol. 39:1608–1618. 2009. View Article : Google Scholar : PubMed/NCBI
18	Tscherner A, Brown AC, Stalker L, Kao J, Dufort I, Sirard MA and LaMarre J: STAT3 signaling stimulates miR-21 expression in bovine cumulus cells during in vitro oocyte maturation. Sci Rep. 8:115272018. View Article : Google Scholar : PubMed/NCBI
19	Fuss IJ, Kanof ME, Smith PD and Zola H: Isolation of whole mononuclear cells from peripheral blood and cord blood. Curr Protoc Immunol Chapter. 7:Unit7.1. 2009.
20	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. View Article : Google Scholar : PubMed/NCBI
21	Banerjee K, Pru C, Pru JK and Resat H: STAT3 knockdown induces tumor formation by MDA-MB-231 cells. Clin Oncol Res. 1:10.31487/j.COR.2018.10.002. 2018.PubMed/NCBI
22	Huang Z, Yang B, Shi Y, Cai B, Li Y, Feng W, Fu Y, Luo L and Wang L: Anti-TNF-α therapy improves Treg and suppresses Teff in patients with rheumatoid arthritis. Cell Immunol. 279:25–29. 2012. View Article : Google Scholar : PubMed/NCBI
23	Yang WY, Shao Y, Lopez-Pastrana J, Mai J, Wang H and Yang XF: Pathological conditions re-shape physiological tregs into pathological tregs. Burns Trauma. 3:12015. View Article : Google Scholar : PubMed/NCBI
24	Saini C, Siddiqui A, Ramesh V and Nath I: Leprosy reactions show increased Th17 cell activity and reduced FOXP3⁺ Tregs with concomitant decrease in TGF-β and increase in IL-6. PLoS Negl Trop Dis. 10:e00045922016. View Article : Google Scholar : PubMed/NCBI
25	Liu C, Yang H, Shi W, Wang T and Ruan Q: MicroRNA-mediated regulation of T helper type 17/regulatory T-cell balance in autoimmune disease. Immunology. 155:427–434. 2018. View Article : Google Scholar : PubMed/NCBI
26	Catalanotto C, Cogoni C and Zardo G: MicroRNA in control of gene expression: An overview of nuclear functions. Int J Mol Sci. 17:17122016. View Article : Google Scholar
27	van der Fits L, van Kester MS, Qin Y, Out-Luiting JJ, Smit F, Zoutman WH, Willemze R, Tensen CP and Vermeer MH: MicroRNA-21 expression in CD4⁺ T cells is regulated by STAT3 and is pathologically involved in Sezary syndrome. J Invest Dermatol. 131:762–768. 2011. View Article : Google Scholar : PubMed/NCBI
28	Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML and Struhl K: STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell. 39:493–506. 2010. View Article : Google Scholar : PubMed/NCBI
29	Almasi-Nasrabadi M, Amoli MM, Robati RM, Rajabi F, Ghalamkarpour F and Gauthier Y: CDH1 and DDR1 common variants confer risk to vitiligo and autoimmune comorbidities. Gene. 700:17–22. 2019. View Article : Google Scholar : PubMed/NCBI
30	Samaka RM, Basha MA and Menesy D: Role of Janus kinase 1 and signal transducer and activator of transcription 3 in vitiligo. Clin Cosmet Investig Dermatol. 12:469–480. 2019. View Article : Google Scholar : PubMed/NCBI
31	Rashighi M and Harris JE: Vitiligo pathogenesis and emerging treatments. Dermatol Clin. 35:257–265. 2017. View Article : Google Scholar : PubMed/NCBI
32	Zhou J, Ling J, Song J, Wang Y, Feng B and Ping F: Interleukin 10 protects primary melanocyte by activation of Stat-3 and PI3K/Akt/NF-κB signaling pathways. Cytokine. 83:275–281. 2016. View Article : Google Scholar : PubMed/NCBI