The role of regulatory T cells in vitiligo and therapeutic advances: a mini-review.

BACKGROUND: Regulatory T cells (Tregs) play vital roles in controlling immune reactions and maintaining immune tolerance in the body. The targeted destruction of epidermal melanocytes by activated CD8+T cells is a key event in the development of vitiligo. However, Tregs may exert immunosuppressive effects on CD8+T cells, which could be beneficial in treating vitiligo. METHODS: A comprehensive search of PubMed and Web of Science was conducted to gather information on Tregs and vitiligo. RESULTS: In vitiligo, there is a decrease in Treg numbers and impaired Treg functions, along with potential damage to Treg-related signaling pathways. Increasing Treg numbers and enhancing Treg function could lead to immunosuppressive effects on CD8+T cells. Recent research progress on Tregs in vitiligo has been summarized, highlighting various Treg-related therapies being investigated for clinical use. The current status of Treg-related therapeutic strategies and potential future directions for vitiligo treatment are also discussed. CONCLUSIONS: A deeper understanding of Tregs will be crucial for advancing Treg-related drug discovery and treatment development in vitiligo.

DCUN1D1, a new molecule involved in depigmentation via upregulating CXCL10.

CD8+ T cells in the lesioned site play a crucial role in the pathogenesis of vitiligo. The chemokine CXCL10 secreted by keratinocytes regulates the migration of CD8+ T cells into the skin. In our previous study, we found that DCUN1D1 expression in vitiligo lesions positively correlates with Cxcl10 expression. In this study, the regulatory effect of DCUN1D1 on CXCL10 and cell function was investigated. DCUN1D1 protein expression was significantly higher in the skin tissue from vitiligo lesions compared with samples from healthy controls. High expression of DCUN1D1 in keratinocytes caused local hair depigmentation in mice, reduced melanin content, high infiltration of CD8+ T cells and increased CXCL10 expression. This suggested that DCUN1D1 may regulate CD8+ T-cell infiltration and depigmentation through CXCL10. Inhibition of DCUN1D1 expression in HaCaT cells abolished the IFN-γ-induced upregulation of p-JAK1, p-STAT1 and CXCL10, suppressed the H2 O2 -induced ROS generation and apoptosis, and upregulated tyrosinase expression in melanocytes. Collectively, these results show that DCUN1D1 is an important regulator of CXCL10 and may be a new target for the treatment of vitiligo.

NAcM-OPT protects keratinocytes from H2O2-induced cell damage by promoting autophagy.

This study aimed to investigate the protective effect of NAcM-OPT, a small molecule inhibitor of defective in cullin neddylation 1 (DCN1), on H2O2-induced oxidative damage in keratinocytes. Immortalized human keratinocytes (HaCaT cells) were treated with NAcM-OPT and exposed to oxidative stress. CCK-8 assays were used to measure cell viability. The mGFP-RFP-LC3 dual fluorescent autophagy indicator system was utilized to evaluate changes in autophagic flux. Western blotting was used to measure the expression of the autophagy-related proteins LC3 and Beclin 1. Keratinocytes were treated with the autophagy activator rapamycin, and HaCaT cell supernatant was added to PIG1 cells (immortalized human melanocytes), followed by evaluation of tyrosinase (TYR) expression via qRT-PCR. NAcM-OPT increased cell viability and cell proliferation. Furthermore, this molecule promoted autophagic flux through increased expression of autophagy-related proteins under H2O2-induced oxidative stress. Additionally, rapamycin increased the mRNA levels of TYR in PIG1 cells. Moreover, NAcM-OPT alleviated mitochondrial damage, restored mitochondrial function, and upregulated the expression of NFE2L2, HO1, NQO1, and GCLM. Importantly, NAcM-OPT also increased epidermal thickness, follicle length, and melanin synthesis under oxidative stress in vivo. These findings suggest that NAcM-OPT may be a promising small molecule antioxidant drug for the treatment of vitiligo.

Crystal structure of plant PLDα1 reveals catalytic and regulatory mechanisms of eukaryotic phospholipase D.

Phospholipase D (PLD) hydrolyzes the phosphodiester bond of glycerophospholipids and produces phosphatidic acid (PA), which acts as a second messenger in many living organisms. A large number of PLDs have been identified in eukaryotes, and are viewed as promising targets for drug design because these enzymes are known to be tightly regulated and to function in the pathophysiology of many human diseases. However, the underlying molecular mechanisms of catalysis and regulation of eukaryotic PLD remain elusive. Here, we determined the crystal structure of full-length plant PLDα1 in the apo state and in complex with PA. The structure shows that the N-terminal C2 domain hydrophobically interacts with the C-terminal catalytic domain that features two HKD motifs. Our analysis reveals the catalytic site, substrate-binding mechanism, and a new Ca2+-binding site that is required for the activation of PLD. In addition, we tested several efficient small-molecule inhibitors against PLDα1, and suggested a possible competitive inhibition mechanism according to structure-based docking analysis. This study explains many long-standing questions about PLDs and provides structural insights into PLD-targeted inhibitor/drug design.