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

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 circR-NAs 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)-g. 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-g 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-g 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.

CircEIF5 contributes to hyperproliferation and inflammation of keratinocytes in psoriasis via p‐NFκB and p‐STAT3 signalling pathway

“…They regulates the proliferation and inflammation of keratinocytes, mesenchymal stem cells (MSCs) and Treg. 13,14,23 However, most researches of circRNAs in psoriasis stayed at the bioinformatic analysis level, the biological function of most circRNAs remains largely unknown. We applied a circRNA microarray to obtain the expression profiles of circRNA in 10 pairs of psoriasis vulgaris lesions and healthy skin tissues.…”

“…There are accumulating evidences that many circRNAs have important biological functions, involving in the initiation and development of a variety of diseases, including cancers, autoimmune disease, metabolic disease 10‐12 . In psoriasis, some circRNAs, such as hsa_circ_0003738and hsa_circ_0061012, have been reported to regular the proliferation, migration and invasion of keratinocytes and dysfunction of Tregs 13,14 …”

“…such as hsa_circ_0003738and hsa_circ_0061012, have been reported to regular the proliferation, migration and invasion of keratinocytes and dysfunction of Tregs. 13,14 To examine the role of circRNAs in psoriatic, We performed a circRNA microarray and validated several circRNAs that were indeed differentially expressed in our previous study 15 (GSE18 1318).…”

circFAM160A2 Promotes Mitochondrial Stabilization and Apoptosis Reduction in Osteoarthritis Chondrocytes by Targeting miR-505-3p and SIRT3

“…They are highly stable because of their covalently closed ring structure, and some of them are evolutionarily conserved [11]. Furthermore, previous studies reported that circRNAs can exert their biological function as microRNA (miRNA) sponges [12,13] and RNAbinding protein sponges [14] and more controversially, through protein translation [15]. The emerging roles of RNA-RNA crosstalk are further confirmed as our knowledge of noncoding RNAs has expanded.…”

circFAM160A2 Promotes Mitochondrial Stabilization and Apoptosis Reduction in Osteoarthritis Chondrocytes by Targeting miR‐505‐3p and SIRT3

“…They are highly stable because of their covalently closed ring structure, and some of them are evolutionarily conserved [ 11 ]. Furthermore, previous studies reported that circRNAs can exert their biological function as microRNA (miRNA) sponges [ 12 , 13 ] and RNA-binding protein sponges [ 14 ] and more controversially, through protein translation [ 15 ]. The emerging roles of RNA-RNA crosstalk are further confirmed as our knowledge of noncoding RNAs has expanded.…”