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

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.

Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function

“…Indeed, Treg specific depletion of miR-21 in mice induced the expression of both IL-17 and IL-10 indicating that miR-21 may play a role in opposing pathways (184). In line with these opposing observations, increased miR-21 expression inhibited FOXP3+ Tregs in human gastric cancer (188) whereas it induced FOXP3 in human and mouse autoimmunity (182,183). Interestingly, LPS stimulation of PBMCs from RA patients down-regulated miR-21; however, PBMCs from healthy controls responded to LPS in the opposite fashion by up-regulating miR-21 (175).…”

“…miR-21, which is among the best studied miRNAs that regulate Tregs in this manner, is dysregulated in several autoimmune disorders in both humans and mice. miR-21 acts indirectly to positively regulate Foxp3 expression (180); however, in autoimmunity, reduced miR-21 expression is correlated with increased STAT3 and reduced STAT5 and Foxp3 expression (26,(181)(182)(183). miR-21 directly targets STAT3 resulting in its downregulation and subsequently reduces effector molecules IL-17 and IL-22 (182,184).…”

“…miR-21 acts indirectly to positively regulate Foxp3 expression (180); however, in autoimmunity, reduced miR-21 expression is correlated with increased STAT3 and reduced STAT5 and Foxp3 expression (26,(181)(182)(183). miR-21 directly targets STAT3 resulting in its downregulation and subsequently reduces effector molecules IL-17 and IL-22 (182,184). Maresin 1 (MaR1) and the EGF/c-Jun pathway have both been shown to induce miR-21, restore Treg : Teff ratios through FOXP3 induction, and reduce autoimmunity (183,185).…”

Update on the role of noncoding RNAs in vitiligo

“…Then, a remarkable reduction in the number and function of regulatory T cells (Tregs) and an increase in CD8+ T cells were found after knocking down miR-155. Another study validated that miR-21-5p expression in PBMCs was downregulated, whereas the expression of signal transducer and activator of transcription 3 (STAT3) was elevated in vitiligo [12] . Further study observed that overexpression of miR-21-5p induced an increase in the Treg/effector T cell (Teff cell) proportion by targeting STAT3.…”

“…Another study validated that miR-21-5p expression in PBMCs was downregulated, whereas the expression of signal transducer and activator of transcription 3 (STAT3) was elevated in vitiligo. [ 12 ] Further study observed that overexpression of miR-21-5p induced an increase in the Treg/effector T cell (Teff cell) proportion by targeting STAT3. Wang et al [ 13 ] found that miR-3940-5p expression was downregulated in the PBMCs of individuals with non-segmental vitiligo.…”