Update on the Role of Noncoding RNAs in Vitiligo
Vitiligo is a prevalent disfiguring skin disorder characterized by the selective absence of functional melanocytes, affecting 0.5% to 1% of the global population. The pathogenesis of vitiligo is complex and involves multiple factors, including autoimmunity, oxidative stress, genetic and environmental factors, and metabolic abnormalities. However, no single factor can fully explain the progression of this disease. Recent studies have highlighted the role of noncoding RNAs (ncRNAs) in the regulation of vitiligo. This article provides a comprehensive update on the role of ncRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in the pathogenesis of vitiligo.
MicroRNAs in Vitiligo
MiRNAs are short ncRNAs, approximately 22 nucleotides in length, that regulate gene expression by binding to the RNA-induced silencing complex (RISC), which then represses transcription or cleaves mRNA. In vitiligo, differential expression profiles of miRNAs have been identified in various sources, including skin lesions, peripheral blood mononuclear cells (PBMCs), serum, and exosomes from keratinocytes. These miRNAs play a significant role in regulating oxidative stress, autoimmunity, and melanocyte biology.
Oxidative Stress and miRNAs
Oxidative stress is a central hypothesis in the pathogenesis of vitiligo. Studies have shown an imbalance between pro-oxidant and antioxidant systems in vitiligo patients. For instance, miR-211 expression is downregulated in the PIG3V vitiligo cell line and skin specimens from vitiligo patients, while its target, PPARG coactivator 1 alpha (PGC1A), is upregulated. Restoration of miR-211 partially reverses the oxygen consumption rates (OCRs) in PIG3V cells, and knockdown of PGC1A reduces elevated reactive oxygen species (ROS) levels to baseline. Additionally, miR-421 is upregulated in an endoplasmic reticulum (ER) stress model of human melanocytes, leading to downregulation of receptor-interacting serine/threonine kinase 1 (RIPK1). Knockdown of miR-421 diminishes ER stress-related apoptosis mediators and activates the PBK/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway, which is associated with cell survival. These findings suggest that miR-421 could be a potential therapeutic target for vitiligo.
Autoimmunity and miRNAs
Vitiligo is also recognized as an autoimmune-related disease. MiR-155 expression is downregulated in T cells of vitiligo patients, leading to a reduction in regulatory T cells (Tregs) and an increase in CD8+ T cells. Similarly, miR-21-5p expression is downregulated in PBMCs, while signal transducer and activator of transcription 3 (STAT3) expression is elevated. Overexpression of miR-21-5p increases the Treg/effector T cell (Teff cell) proportion by targeting STAT3. Another study found that miR-3940-5p expression is downregulated in PBMCs of non-segmental vitiligo patients, leading to increased T-cell numbers and interleukin 2 receptor subunit gamma (IL-2RG) levels. These findings indicate that the miR-3940-5p-IL-2RG axis may affect T-cell proliferation and contribute to vitiligo development.
Melanocyte Biology and miRNAs
Dysregulated melanocyte biology, influenced by genetic and nongenetic factors, ultimately leads to depigmentation in vitiligo. MiR-21-5p expression is higher in vitiligo patients than in controls, and its overexpression in melanocytes reduces the expression of SRY (sex-determining region Y)-box 5 (SOX5), b-catenin, and cyclin-dependent kinase 2, while increasing microphthalmia-associated transcription factor expression. This suggests that miR-21-5p may serve as a compensatory mechanism for melanocytes, although it is insufficient to counterbalance other detrimental mechanisms. Additionally, transfection of six miRNAs (miR-185, miR-202, miR-525-5p, miR-326, miR-518a-5p, and miR-518c) upregulated in vitiligo lesions inversely downregulates tyrosinase-related protein 1 (TRP1) expression in normal human epidermal keratinocytes. The TT genotype of miR-196a-2 is prevalent in vitiligo patients and may alter tyrosinase (TYR) expression, affecting susceptibility to vitiligo and therapeutic response. Exosomes secreted by keratinocytes from vitiligo lesions (VLKs) show decreased miR-200c levels, leading to higher SOX1 expression in melanocytes, which downregulates b-catenin expression and suppresses melanogenesis-related genes. Exosomes from keratinocytes overexpressing miR-330-5p also reduce melanin production and TYR expression in melanocytes. Furthermore, the p53-transient receptor potential cation channel subfamily M member 1/miR-211-matrix metalloprotease 9 axis plays a role in melanocyte migration, potentially improving repigmentation outcomes in vitiligo patients. Elevated miR-9 levels in vitiligo skin lesions reduce E-cadherin and b1 integrin levels, but ultraviolet B (UVB) treatment reverses this state, recovering the adhesion function of keratinocytes and facilitating melanocyte migration.
Long Non-Coding RNAs in Vitiligo
LncRNAs are ncRNAs longer than 200 nucleotides. Research on lncRNAs in vitiligo is emerging, with several lncRNAs implicated in the disease. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an 8000 nucleotide-long lncRNA that regulates mRNA splicing, transcription, and functions as a competitive endogenous RNA. Increased MALAT1 and decreased miR-211 expression in VLKs suggest that MALAT1 binds to miR-211, suppressing its expression and increasing sirtuin 1 (SIRT1) levels. SIRT1 protects keratinocytes from UVB-induced DNA damage, which may explain why patients with skin cancer are less susceptible to vitiligo. Taurine-upregulated gene 1 (TUG1) expression is decreased in vitiligo patients and positively related to the time of appearance of the last lesion, indicating a relationship between TUG1 and vitiligo activity. Additionally, plasmacytoma variant translocation 1 (PVT1) SNP rs10087240 is significantly associated with vitiligo, confirming PVT1 as a vitiligo susceptibility locus in the European population.
Circular RNAs in Vitiligo
CircRNAs are a unique type of ncRNA characterized by a closed-loop structure. Recent studies have identified circRNA-miRNA-mRNA regulatory networks that may play a crucial role in vitiligo pathology. For example, the circ_0087961-miR-27a-3p-PAXILLIN axis is related to vitiligo. Paxillin, a 69-kDa adapter protein, promotes melanocyte adhesion, suggesting that this regulatory network may be involved in the pathogenesis of vitiligo.
Conclusion
Research on the role of ncRNAs in vitiligo is still in its early stages, particularly for lncRNAs and circRNAs. However, accumulating evidence supports the potential of ncRNAs in regulating oxidative stress, autoimmunity, and melanocyte biology in vitiligo. MiRNAs derived from exosomes are increasingly recognized for their role in intercellular communication. As theoretical studies progress, ncRNAs may offer new diagnostic and therapeutic options for vitiligo in the future.
doi.org/10.1097/CM9.0000000000001900
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