Positive-Negative Feedback Loop between Mir-197 and IL-17A Signaling in Human Keratinocytes

Abstract

Psoriasis is a chronic inflammatory skin disorder which results from pathological interactions between activated immunocytes and keratinocytes. Recent studies implicated the role of IL-17 and IL-22, secreted from Th17 and Th22 in the generation and propagation of the psoriatic plaque. Previously, we and others have shown that the expression of miR-197 is significantly decreased in psoriatic lesions. We further showed that miR-197 targets IL-22RA1 and that ectopic expression of miR-197 prevent IL-22 induced proliferation and migration of keratinocytes.Since the 3'UTR of the IL17RA subunit mRNA contains a putative binding site for miR-197, our aim was to expand our understanding of the miRNA-mediated crosstalk between immunocytes and keratinocytes by studying the effect of miR-197 expression on IL-17A signaling pathway. Luciferase reporter assays along with Western blot analysis revealed that miR-197 directly targets the 3'UTR of IL17RA. Furthermore, ectopic expression of miR-197 led to a significant decrease in IL-17A-induced expression of CCL20, a known downstream effector of IL-17A. Interestingly, the addition of IL-17A to keratinocytes led to a rapid and transient increase in the expression of miR-197. Chromatin immuno-precipitation assays showed that keratinocytes' treatment with IL-17 leads to C/EBP binding to the promoter region of miR-197, and that the expression level of miR-197 is directly proportional to the extent of C/EBP binding to the promoter. Moreover, following treatment with IL-17A, the histone acetylation pattern at the miR-197 promoter turns to become characteristic of transcribed chromatin.Taken together, our results suggest that a positive-negative feedback loop exists between IL-17A and miR-197 in keratinocytes; the cytokine induces the binding of C/EBPα to miR-197 promoter sequences, enhances miR-197 expression that negatively attenuates IL-17 receptor and decreases the input along the IL-17A pathway. Our work suggests that in psoriasis, decreased expression of miR-197 may prevent the miR-197-induced attenuation of the IL-17 cascade, leading to its over-activity.

Is microRNA 1910-3p (miR-1910-3p) a really distinctive marker for psoriasis?

“…miRs usually bind to the 3'UTR region on the target mRNA, causing either the degradation of the mRNA sequence or an inhibition of its translation [5]. Previous studies have evaluated the levels of miR-1266, miR-340 and miR-197, which are thought to act via IL-17A in patients with psoriasis [12][13][14][15]. In two studies, miR1266 were found to be significantly higher in plaque psoriasis patients than in healthy controls and showed a correlation with PASI, suggested that the effect of miR-1266 on the pathogenesis of psoriasis was not through a regulation of IL-17A expression but through a more upstream signaling mechanism or miR-1266 is not likely to regulate IL-17A expression directly, but may be involved in the pathogenesis of psoriasis by regulating other target molecules [12][13].…”

“…Bian et al have shown that miR-340 can bind specifically to the 3'UTR region of IL-17A and reduce endogenous IL-17A expression in mouse skin with psoriasis [14]. Elharrar et al reported that miR-197 expression was lower in psoriatic skin keratinocytes than in the healthy skin, suggesting that a decrease in the suppression of the IL-17A pathway may lead to an accelerated proinflammatory process [15]. In our study, plasma levels of miR-1910-3p (targets IL-17A mRNA) were found to be significantly lower in the patient group compared to the controls (p = 0.000, fc: 0.10).…”

Understanding psoriasis: Role of miRNAs (Review)

“…It binds onto the IL-22RA1 subunit of IL-22, leading to hyperproliferation ( 37 ). It can also bind to the IL-17RA subunit of the IL-17R, thus promoting normal proliferation and decreasing the process of abnormal differentiation ( 38 ). By inhibiting IL-17RA in keratinocytes, miR-197 reduces the expression of CCL, a chemoattractant for dendritic cells and T lymphocytes ( 37 ).…”

Advances in the Application and Impact of MicroRNAs as Therapies for Skin Disease

“…Among the dysregulated miRNAs detected in all four studies, miR-203 was consistently observed to be upregulated, from which it can be inferred that miR-203 is an important factor in the pathogenesis of psoriasis and could be a potential therapeutic target. Both interleukin-17 receptor (IL-17R) and IL-22R have been shown to be involved the pathogenesis of psoriasis, which is interesting in that miR-197 was found to be downregulated in the miRNA-profiling effort with psoriatic skin (Table 1 ) and miR-197 is reportedly antagonistic to IL-17R and IL-22R [ 48 , 52 , 53 ]. Additional studies have examined whether differentially regulated miRNAs contribute to the effectiveness of photochemotherapy and phototherapy in treating psoriatic skin.…”