hsa_circ_0003738 Inhibits the Suppressive Function of Tregs by Targeting miR-562/IL-17A and miR-490-5p/IFN-γ Signaling Pathway

Luting Yang; Chen Zhang; Xiaocui Bai; Chunying Xiao; Erle Dang; Gang Wang

doi:10.1016/j.omtn.2020.08.001

hsa_circ_0003738 Inhibits the Suppressive Function of Tregs by Targeting miR-562/IL-17A and miR-490-5p/IFN-γ Signaling Pathway

Mol Ther Nucleic Acids. 2020 Sep 4:21:1111-1119. doi: 10.1016/j.omtn.2020.08.001. Epub 2020 Aug 5.

Authors

Luting Yang¹, Chen Zhang², Xiaocui Bai², Chunying Xiao², Erle Dang², Gang Wang³

Affiliations

¹ Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, No. 620, South Chang'an Road, Xi'an 710062, China.
² Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
³ Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: xjwgang@fmmu.edu.cn.

Abstract

Dysfunction in the suppressive function of regulatory T cells (Tregs) has been related to the pathogenesis of psoriasis. Accumulating evidence has demonstrated the importance of circular RNAs (circRNAs) in regulating various biological process, such as cell proliferation, apoptosis, etc. However, the role of circRNAs in modulating the suppressive functions of psoriatic Tregs and the underlying mechanisms have not been investigated. Here, by using circRNA microarray analysis, we discovered four upregulated and four downregulated circRNAs in psoriatic Tregs. Quantitative real-time PCR further confirmed a significant increase of circ_0003738 in psoriatic Tregs. Importantly, knockdown of circ_0003738 by lentivirus in psoriatic Tregs could restore their suppressive functions via inhibiting the secretion of proinflammatory cytokines interleukin-17A (IL-17A) and interferon (IFN)-γ. Moreover, we found that circ_0003738 could bind to miR-562 to release the inhibition of target gene IL-17RA (IL-17 receptor A), thus promoting IL-17A signaling in psoriatic Tregs. In parallel, circ_0003738 acted also as a sponge for miR-490-5p and relieved inhibition for the target gene IFNGR2, which promoted IFN-γ signaling in psoriatic Tregs. Our study demonstrated that upregulated circ_0003738 decreased the suppressive function of psoriatic Tregs via the miR-562/IL17RA and miR-490-5p/IFNGR2 (IFN-γ receptor 2) axis, which indicated the involvement of circRNAs in the pathogenesis of dysfunctional Tregs. These findings will provide new therapeutic targets for the treatment of psoriasis.

Keywords: IFN-γ; IL-17A; circular RNA; miR-490-5p; miR-562; psoriasis; regulatory T cells.