Exosomes: The emerging mechanisms and potential clinical applications in dermatology.

Skin tissue, composed of epidermis, dermis, and subcutaneous tissue, is the largest organ of the human body. It serves as a protective barrier against pathogens and physical trauma and plays a crucial role in maintaining homeostasis. Skin diseases, such as psoriasis, dermatitis, and vitiligo, are prevalent and can seriously impact the quality of patient life. Exosomes are lipid bilayer vesicles derived from multiple cells with conserved biomarkers and are important mediators of intercellular communication. Exosomes from skin cells, blood, and stem cells, are the main types of exosomes that are involved in modulating the skin microenvironment. The dysregulation of exosome occurrence and transmission, as well as alterations in their cargoes, are crucial in the complex pathogenesis of inflammatory and autoimmune skin diseases. Therefore, exosomes are promising diagnostic and therapeutic targets for skin diseases. Importantly, exogenous exosomes, derived from skin cells or stem cells, play a role in improving the skin environment and repairing damaged tissues by carrying various specific active substances and involving a variety of pathways. In the domain of clinical practice, exosomes have garnered attention as diagnostic biomarkers and prospective therapeutic agents for skin diseases, including psoriasis and vitiligo. Furthermore, clinical investigations have substantiated the regenerative efficacy of stem cell-derived exosomes in skin repair. In this review, we mainly summarize the latest studies about the mechanisms and applications of exosomes in dermatology, including psoriasis, atopic dermatitis, vitiligo, systemic lupus erythematosus, systemic sclerosis, diabetic wound healing, hypertrophic scar and keloid, and skin aging. This will provide a novel perspective of exosomes in the diagnosis and treatment of dermatosis.

Exosomes containing miR-1469 regulate natural killer cells by targeting CD122 in non-segmental vitiligo.

BACKGROUND: Plasma exosomal microRNAs (miRNAs) have been used as potential biomarkers for various diseases and have been investigated for their possible involvement in the pathogenesis of vitiligo. However, the miRNA expression profile of plasma exosomes in patients with non-segmental vitiligo (NSV) has not been determined yet. OBJECTIVE: To screen differentially expressed microRNAs in plasma exosomes derived from patients with NSV and explore their roles in the pathogenesis of NSV. METHODS: High-throughput sequencing was performed to determine the expression profiles of exosomal miRNAs in NSV. The effect of upregulated miR-1469 in NSV circulating exosomes on natural killer (NK) cells was further investigated using various molecular biological techniques. RESULTS: MiR-1469 was identified as a candidate biomarker whose expression was significantly increased in circulating exosomes of NSV patients. Circulating exosomes were internalized by NK cells and increased NK cell proliferation viability and IFN-γ secretion capacity delivering miR-1469. Further studies revealed that the upregulation of CD122, the predicted target of miR-1469, could partially reverse the effect of miR-1469 on natural killer cells. CONCLUSION: Alterations in plasma exosomal cargo occur in NSV and appear to contribute to NK cell dysfunction. Exosomal miR-1469 may be a biomarker of disease activity and could be used as a therapeutic drug target against innate immunity in NSV patients. The present study provides new insights into the role of exosomal miRNAs in NSV and suggests a novel miR-1469-CD122-IFN-γ pathway of NK cell underlying pathogenesis of NSV.

The role of aryl hydrocarbon receptor in vitiligo: a review.

Vitiligo is an acquired autoimmune dermatosis characterized by patchy skin depigmentation, causing significant psychological distress to the patients. Genetic susceptibility, environmental triggers, oxidative stress, and autoimmunity contribute to melanocyte destruction in vitiligo. Due to the diversity and complexity of pathogenesis, the combination of inhibiting melanocyte destruction and stimulating melanogenesis gives the best results in treating vitiligo. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that can regulate the expression of various downstream genes and play roles in cell differentiation, immune response, and physiological homeostasis maintenance. Recent studies suggested that AhR signaling pathway was downregulated in vitiligo. Activation of AhR pathway helps to activate antioxidant pathways, inhibit abnormal immunity response, and upregulate the melanogenesis gene, thereby protecting melanocytes from oxidative stress damage, controlling disease progression, and promoting lesion repigmentation. Here, we review the relevant literature and summarize the possible roles of the AhR signaling pathway in vitiligo pathogenesis and treatment, to further understand the links between the AhR and vitiligo, and provide new potential therapeutic strategies.

TRPM2-dependent autophagy inhibition exacerbates oxidative stress-induced CXCL16 secretion by keratinocytes in vitiligo.

Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte-derived chemokine C-X-C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2-mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12-Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank-binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2-restrained autophagy promotes CXCL16 secretion via the Atg5-TBK1-IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.

Melanogrit potentiates melanogenesis by escalating cellular tyrosinase activity and MITF levels via pERK inhibition.

Vitiligo is characterized by the development of white patches on the skin either due to the loss of functional melanocytes or perturbations in the melanogenesis pathway. In the present study, we investigated the therapeutic potential of herbo-mineral formulation, Melanogrit in neutralizing the white patches in the skin. The study utilized UPLC/MS-QToF technique to determine the diversified phytochemical profile in Melanogrit. The murine B16F10 cells when treated with Melanogrit underwent morphological changes, including increased angularity, enlarged cell size, and greater dendritic protrusions. To establish an equivalent model to study melanogenesis, we carefully optimized the dosage of α-melanocyte stimulating hormone (αMSH) in B16F10 cells as an alternative to using melanocyte-keratinocyte cocultures. The study determined a sub-optimal dose of αMSH (0.2 nM) in B16F10 cells that does not manifest any measurable effects on melanogenesis. In contrast, Melanogrit when used in conjunction with 0.2 nM αMSH, induced a dose-dependent increase in extracellular and intracellular melanin levels. Melanogrit transcriptionally up-regulated the decisive genes of the melanogenesis pathway, MITF, TYR, and TRP1, which was evident from the increased cellular tyrosine activity. Our findings also demonstrated that Melanogrit ameliorated the MITF protein levels by inhibiting pERK; notably without involving GSK3ß in the process. Taken together, our findings strongly suggest that Melanogrit has the potential to stimulate melanogenesis, making it a promising candidate for clinical applications in the treatment of white skin patches that develop in vitiligo patients.

Compromised melanocyte survival due to decreased suppression of CD4+ & CD8+ resident memory T cells by impaired TRM-regulatory T cells in generalized vitiligo patients.

Regulatory T cells (Tregs) are involved in the suppression of activated T cells in generalized vitiligo (GV). The study was aimed to investigate resident memory (TRM)-Tregs and antigen-specific Tregs' numbers and functional defects in 25 GV patients and 20 controls. CD4+ & CD8+ TRM cell proliferation was assessed by BrDU assay; production of IL-10, TGF-ß, IFN-γ, perforin and granzyme B were assessed by ELISA and enumeration of TRM cells was done by flowcytometry. GV patients showed significantly increased frequency and absolute count of CD4+ & CD8+ TRM cells in lesional (L), perilesional (PL) and non-lesional (NL) skin compared to controls (p = 0.0003, p = 0.0029 & p = 0.0115, respectively & p = 0.0003, p = 0.003 & p = 0.086, respectively). Whereas, TRM-Treg (p < 0.0001 & p = 0.0015) and antigen-specific Tregs (p = 0.0014 & p = 0.003) exhibited significantly decreased frequency and absolute counts in L & PL skin. GV patients showed reduced suppression of CD8+ & CD4+ TRM cells (with increased IFN-γ, perforin & granzyme B) and decreased TRM-Tregs and antigen-specific Tregs (with decreased IL-10 & TGF-ß production) and reduced proliferation of SK-Mel-28 cells in co-culture systems. Immunohistochemistry revealed increased expression of TRM stimulating cytokines: IL-15 & IL-17A and reduced expression of TGF-ß & IL-10 in L, PL, NL skins compared to controls. These results for the first time suggest that decreased and impaired TRM-Tregs and antigen-specific Tregs are unable to suppress CD4+ & CD8+ TRMs' cytotoxic function and their proliferation due to decrease production of immunosuppressive cytokines (IL-10 & TGF-ß) and increased production of TRM based IFN-γ, perforin and granzyme B production, thus compromising the melanocyte survival in GV.

The underestimated role of mitochondria in vitiligo: From oxidative stress to inflammation and cell death.

Vitiligo is an acquired depigmentary disorder characterized by the depletion of melanocytes in the skin. Mitochondria shoulder multiple functions in cells, such as production of ATP, maintenance of redox balance, initiation of inflammation and regulation of cell death. Increasing evidence has implicated the involvement of mitochondria in the pathogenesis of vitiligo. Mitochondria alteration will cause the abnormalities of mitochondria functions mentioned above, ultimately leading to melanocyte loss through various cell death modes. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in mitochondrial homeostasis, and the downregulation of Nrf2 in vitiligo may correlate with mitochondria damage, making both mitochondria and Nrf2 promising targets in treatment of vitiligo. In this review, we aim to discuss the alterations of mitochondria and its role in the pathogenesis of vitiligo.

Extraciliary OFD1 Is Involved in Melanocyte Survival through Cell Adhesion to ECM via Paxillin.

Primary cilia play a significant role in influencing cell fate, including apoptosis in multiple cell types. In the lesional epidermis of vitiligo patients, a reduced number of ciliated cells was observed. Our study also revealed a downregulation of oral-facial digital syndrome type 1 (OFD1) in the affected skin of vitiligo patients. However, it remains unknown whether primary cilia are involved in the control of melanocyte apoptosis. While both intraflagellar transport 88 (IFT88) and retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L) are associated with ciliogenesis in melanocytes, only the knockdown of OFD1, but not IFT88 and RPGRIP1L, resulted in increased melanocyte apoptosis. OFD1 knockdown led to a decrease in the expression of proteins involved in cell-extracellular matrix (ECM) interactions, including paxillin. The OFD1 amino acid residues 601-1012 interacted with paxillin, while the amino acid residues 1-601 were associated with ciliogenesis, suggesting that the OFD1 domains responsible for paxillin binding are distinct from those involved in ciliogenesis. OFD1 knockdown, but not IFT88 knockdown, inhibited melanocyte adhesion to the ECM, a defect that was restored by paxillin overexpression. In summary, our findings indicate that the downregulation of OFD1 induces melanocyte apoptosis, independent of any impairment in ciliogenesis, by reducing melanocyte adhesion to the ECM via paxillin.

Oxidative Stress and Potential Antioxidant Therapies in Vitiligo: A Narrative Review.

Vitiligo is a chronic skin disorder characterised by the loss of melanocytes and subsequent skin depigmentation. Although many theories have been proposed in the literature, none alone explains the pathogenesis of vitiligo. Oxidative stress has been identified as a potential factor in the pathogenesis of vitiligo. A growing body of evidence suggests that antioxidant therapies may offer a promising approach to managing this condition. This review summarises the potential mechanisms of oxidative stress and the types of melanocyte death in vitiligo. We also provide a brief overview of the most commonly studied antioxidants. Melanocytes in vitiligo are thought to be damaged by an accumulation of reactive oxygen species to destroy the structural and functional integrity of their DNA, lipids, and proteins. Various causes, including exogenous and endogenous stress factors, an imbalance between prooxidants and antioxidants, disruption of antioxidant pathways, and gene polymorphisms, lead to the overproduction of reactive oxygen species. Although necroptosis, pyroptosis, ferroptosis, and oxeiptosis are newer types of cell death that may contribute to the pathophysiology of vitiligo, apoptosis remains the most studied cell death mechanism in vitiligo. According to studies, vitamin E helps to treat lipid peroxidation of the skin caused by psoralen ultra-violet A treatment. In addition, Polypodium leucotomos increased the efficacy of psoralen ultra-violet A or narrow-band ultraviolet B therapy. Our review provides valuable insights into the potential role of oxidative stress in pathogenesis and antioxidant-based supporting therapies in treating vitiligo, offering a promising avenue for further research and the development of effective treatment strategies.

Pharmacological inhibition of demethylzeylasteral on JAK-STAT signaling ameliorates vitiligo.

BACKGROUND: The activation of CD8+ T cells and their trafficking to the skin through JAK-STAT signaling play a central role in the development of vitiligo. Thus, targeting this key disease pathway with innovative drugs is an effective strategy for treating vitiligo. Natural products isolated from medicinal herbs are a useful source of novel therapeutics. Demethylzeylasteral (T-96), extracted from Tripterygium wilfordii Hook F, possesses immunosuppressive and anti-inflammatory properties. METHODS: The efficacy of T-96 was tested in our mouse model of vitiligo, and the numbers of CD8+ T cells infiltration and melanocytes remaining in the epidermis were quantified using whole-mount tail staining. Immune regulation of T-96 in CD8+ T cells was evaluated using flow cytometry. Pull-down assay, mass spectrum analysis, molecular docking, knockdown and overexpression approaches were utilized to identify the target proteins of T-96 in CD8+ T cells and keratinocytes. RESULTS: Here, we found that T-96 reduced CD8+ T cell infiltration in the epidermis using whole-mount tail staining and alleviated the extent of depigmentation to a comparable degree of tofacitinib (Tofa) in our vitiligo mouse model. In vitro, T-96 decreased the proliferation, CD69 membrane expression, and IFN-γ, granzyme B, (GzmB), and perforin (PRF) levels in CD8+ T cells isolated from patients with vitiligo. Pull-down assays combined with mass spectrum analysis and molecular docking showed that T-96 interacted with JAK3 in CD8+ T cell lysates. Furthermore, T-96 reduced JAK3 and STAT5 phosphorylation following IL-2 treatment. T-96 could not further reduce IFN-γ, GzmB and PRF expression following JAK3 knockdown or inhibit increased immune effectors expression upon JAK3 overexpression. Additionally, T-96 interacted with JAK2 in IFN-γ-stimulated keratinocytes, inhibiting the activation of JAK2, decreasing the total and phosphorylated protein levels of STAT1, and reducing the production and secretion of CXCL9 and CXCL10. T-96 did not significantly inhibit STAT1 and CXCL9/10 expression following JAK2 knockdown, nor did it suppress upregulated STAT1-CXCL9/10 signaling upon JAK2 overexpression. Finally, T-96 reduced the membrane expression of CXCR3, and the culture supernatants pretreated with T-96 under IFN-γ stressed keratinocytes markedly blocked the migration of CXCR3+CD8+ T cells, similarly to Tofa in vitro. CONCLUSION: Our findings demonstrated that T-96 might have positive therapeutic responses to vitiligo by pharmacologically inhibiting the effector functions and skin trafficking of CD8+ T cells through JAK-STAT signaling.

Restraint stress promotes monobenzone-induced depigmentation in mice via the activation of glucocorticoid receptor/macrophage migration inhibitory factor signaling pathway.

Psychological stress triggers onset and development of vitiligo in humans. However, the mechanism of psychological stress on vitiligo remains unclear. The study aims to investigate whether psychological stress promotes vitiligo and explore the underlying mechanism. A depigmentation mouse model induced by applying a skin-bleaching reagent monobenzone to dorsal skin and an in vitro HaCaT keratinocyte death model induced by monobenzone were employed to explore the effect of restraint stress, which mimics psychological stress, on depigmentation. The results indicated that restraint stress promoted vitiligo-related depigmentation, vacuolisation, spongiosis, CD8+ T lymphocyte infiltration, and loss of melanocytes in the skin. Restraint stress activated cutaneous NLR family containing pyrin domain protein 3 (NLRP3) inflammasome. In addition, restraint stress aggravated anxiety-like behaviors and increased levels of macrophage migration inhibitory factor (MIF) and corticosterone in the circulation, accompanied with decreasing the expression of cutaneous 8-oxoguanine DNA glycosylase (OGG1) in depigmentation mice. In vitro experiments demonstrated that activation of glucocorticoid receptor (GR) by cortisol upregulated NLRP3 expression dependent on MIF, and directly decreased the transcription of OGG1. Blockade of MIF reversed the NLRP3 signal in restraint stress-induced depigmentation mice. In conclusion, restraint stress promotes vitiligo-related depigmentation in mice via the activation of GR/MIF signaling pathway. The findings provide a theoretical basis for prevention and treatments of vitiligo with therapies of targeting GR, MIF, and OGG1.

Impact of house dust mite in vitiligo skin: environmental contribution to increased cutaneous immunity and melanocyte detachment.

BACKGROUND: Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte intrinsic dysfunction may directly contribute to melanocyte loss. House dust mite (HDM), an environmental allergen with potent protease activity, contributes to respiratory and gut disease but also to atopic dermatitis and rosacea. OBJECTIVES: To verify if HDM can contribute to melanocyte detachment in vitiligo and if so, by which mechanism(s). METHODS: Using primary human keratinocytes, human skin biopsies from healthy donors and patients with vitiligo, and 3D reconstructed human epidermis, we studied the effect of HDM on cutaneous immunity, tight and adherent junction expression and melanocyte detachment. RESULTS: HDM increased keratinocyte production of vitiligo-associated cytokines and chemokines and increased expression of toll-like receptor (TLR)-4. This was associated with increased in situ matrix-metalloproteinase (MMP)-9 activity, reduced cutaneous expression of adherent protein E-cadherin, increased soluble E-cadherin in culture supernatant and significantly increased number of suprabasal melanocytes in the skin. This effect was dose-dependent and driven by cysteine protease Der p1 and MMP-9. Selective MMP-9 inhibitor, Ab142180, restored E-cadherin expression and inhibited HDM-induced melanocyte detachment. Keratinocytes from patients with vitiligo were more sensitive to HDM-induced changes than healthy keratinocytes. All results were confirmed in a 3D model of healthy skin and in human skin biopsies. CONCLUSIONS: Our results highlight that environmental mite may act as an external source of pathogen-associated molecular pattern molecules in vitiligo and topical MMP-9 inhibitors may be useful therapeutic targets. Whether HDM contributes to the onset of flares in vitiligo remains to be tested in carefully controlled trials.

Silk Fibroin-Based Hydrogel Microneedles Deliver α-MSH to Promote Melanosome Delivery for Vitiligo Treatment.

Microneedles have shown great advantages in subcutaneous drug delivery and skin disease treatment. Vitiligo is a difficult-to-cure skin disease characterized by the depigmentation of the epidermis. Melanosomes produced in melanocytes are transported through dendrites to adjacent keratinocytes, where they accumulate, resulting in skin pigmentation. However, melanocytes in vitiligo patients are functionally disrupted. Silk fibroin (SF) methacrylate hydrogel microneedle can deliver α-MSH to the epidermis directly, where α-MSH helps the protection of melanocytes, extension of melanocytic dendrites, and transfer of melanosomes. In addition, the expression of melanogenesis-related melanocyte-inducing transcription factor and tyrosinase-related protein 1 (TRP1) was up-regulated, and the number of hair follicle stem cells increased with good proliferative activity. This slow release α-MSH SF-based hydrogel microneedles provides a new idea for the treatment of vitiligo.

Ubiquitin-specific protease 34 in macrophages limits CD8 T cell-mediated onset of vitiligo in mice.

As an autoimmune disorder, vitiligo is characterized by depigmented skin macules. CD8+T cells and macrophages enrichment promote the onset of vitiligo, while the role of macrophages to CD8+T is not well deciphered. To develop a mouse model of vitiligo with prominent epidermal depigmentation, Krt14-Kitl* transgenic mice containing an elevated number of melanocytes in the epidermis with membrane-bound Kit ligand (Kitl*) were adoptively transferred with premelanosome protein (PMEL) CD8+ T cells. On the other hand, Krt14-Kitl* mice were mated with ubiquitin-specific protease 34 (USP34)MKO mice to decipher the role of USP34 in vitiligo. Vitiligo scores and PMEL CD8+ T cell enrichment were detected with flow cytometry. Human peripheral blood mononuclear cells (PBMCs) or mice bone marrow-derived macrophages (BMDMs) were incubated with lipopolysaccharide (LPS), CpG, or co-incubated with KU-55933, an ataxia telangiectasia-mutated (ATM) inhibitor. Chemokine (C-C motif) ligand 2 (CCL2), Ccl5, and interleukin (Il)-12α expression was assayed with real-time PCR, and p-IKKα/ß was assayed with Western blots. USP34 was up-regulated in the PBMCs of vitiligo patients and LPS-stimulated BMDMs. USP34 deficiency did not affect the differentiation of CD11b+F4/80+ macrophages in the bone marrow. Immunoprecipitation demonstrated the interaction between USP34 and ATM. USP34 deficiency or KU-55933 administration promoted the induction of Ccl2, Ccl5, Il12α, and p-IKKα/ß in LPS or CpG stimulated BMDMs; KU-55933 administration could not affect the expression of the above molecules in USP34 deficient BMDMs. It further revealed that USP34 deficiency promoted the development of vitiligo with increased PMEL CD8+ T cell enrichment, which was not affected by KU-55933 administration. USP34 deficiency in macrophages promotes the onset of vitiligo with increased PMEL CD8+ T cell enrichment, and USP34/ATM complex can be considered as a therapy target.

The possible role of Wnt/ß-catenin signalling in vitiligo treatment.

Vitiligo is a common chronic skin disease which has an adverse impact on patients' life. Its pathogenesis is complex, involving autoimmunity and oxidative stress (OS). Autoimmunity leads to the loss of epidermal melanocytes and the formation of the depigmented patches of the disease. Treatment of vitiligo should control the exaggerated immune response to arrest the progress of active disease, and then promote melanocytes to repigmentation. Wnt/ß-catenin signalling pathway has been of recent interest in vitiligo. Wnt/ß-catenin signalling pathway is downregulated in vitiligo. Upregulation of Wnt/ß-catenin signalling possibly control vitiligo autoimmune response by protecting melanocyte from OS damage, inhibiting CD8+ T cell effector cell differentiation and enhancing Treg. Wnt/ß-catenin signalling plays a critical role in the melanocyte regeneration by driving the differentiation of melanocyte stem cells (McSCs) into melanocytes. Promoting Wnt/ß-catenin signalling can not only arrest the progress of active disease of vitiligo but also promote repigmentation. Some of the main effective therapies for vitiligo are likely to work by activating Wnt/ß-catenin signalling. Agents that can enhance the effect of Wnt/ß-catenin signalling may become potential candidates for the development of new drugs for vitiligo treatment.

Evidence for Epistatic Interaction between HLA-G and LILRB1 in the Pathogenesis of Nonsegmental Vitiligo.

Vitiligo is the most frequent cause of depigmentation worldwide. Genetic association studies have discovered about 50 loci associated with disease, many with immunological functions. Among them is HLA-G, which modulates immunity by interacting with specific inhibitory receptors, mainly LILRB1 and LILRB2. Here we investigated the LILRB1 and LILRB2 association with vitiligo risk and evaluated the possible role of interactions between HLA-G and its receptors in this pathogenesis. We tested the association of the polymorphisms of HLA-G, LILRB1, and LILRB2 with vitiligo using logistic regression along with adjustment by ancestry. Further, methods based on the multifactor dimensionality reduction (MDR) approach (MDR v.3.0.2, GMDR v.0.9, and MB-MDR) were used to detect potential epistatic interactions between polymorphisms from the three genes. An interaction involving rs9380142 and rs2114511 polymorphisms was identified by all methods used. The polymorphism rs9380142 is an HLA-G 3'UTR variant (+3187) with a well-established role in mRNA stability. The polymorphism rs2114511 is located in the exonic region of LILRB1. Although no association involving this SNP has been reported, ChIP-Seq experiments have identified this position as an EBF1 binding site. These results highlight the role of an epistatic interaction between HLA-G and LILRB1 in vitiligo pathogenesis.

Pathogenic Th2 Cytokine Profile Skewing by IFN-γ-Responding Vitiligo Fibroblasts via CCL2/CCL8.

PURPOSE: Vitiligo is a T cell-mediated skin depigmentation disease. Though treatments arresting disease progression and inducing repigmentation are available, the efficacy of these options is often limited and poorly sustained. How stromal signals contribute to the interferon-γ-dominant skin niches is unclear. This study aims to determine how fibroblasts participate in the IFN-γ-dominant vitiligo niche. PATIENTS AND METHODS: Mouse vitiligo models were established. Fibroblasts from control and vitiligo mice were extracted for RNA sequencing. In vitro IFN-γ stimulation was performed to verify the JAK-STAT pathway by qPCR and Western blot. T cell polarization with chemokines was measured by flow cytometry. Protein levels in tissues were also examined by IHC. RESULTS: The vitiligo mouse model recapitulates the human CD8-IFN-γ pathway. RNA sequencing revealed elevated chemokine CCL2 and CCL8 in vitiligo fibroblast, which may be regulated by the JAK-STAT signaling. Such phenomenon is verified by JAK inhibitor peficitinib in vitro. Moreover, CCL2 addition into the naïve T polarization system promoted type 2 cytokines secretion, which represents a hallmark of vitiligo lesions. CONCLUSION: Dermal fibroblasts, a principal constituent of skin structure, respond to IFN-γ by skewing T cells towards a type 2 cytokine profile via CCL2 and CCL8, which can be abrogated by JAK inhibitor peficitinib.

Melanocyte Adhesion and Apoptosis in Vitiligo: Linking Puzzle Blocks.

Vitiligo is the utmost common depigmenting condition consequential from melanocyte loss from the basal layer of the epidermis. Vitiligo disease mostly affects dark-skinned races and makes them more sensitive to UV radiation. It is also linked with some autoimmune diseases and various psychosocial difficulties. Melanocyte loss leads to depigmentation in vitiligo, is a major concern over decades, and even affects an individual's day-to-day life severely. All the theories, including autoimmune, autocytotoxic, and neural, collectively decipher either prime impact on the melanogenesis inhibition or deficient adhesion inspired melanocytes disappearance. Previously it has been described that melanocyte loss in vitiligo patients is caused by defective adhesion. Melanocyte death by apoptosis mainly occurs due to melanocyte detachment or migration from the basal layer and further followed by transepidermal migration. Various cell surface molecules, i.e., cell adhesion molecules (CAMs) in affiliation with neighbouring cells and extracellular matrix (ECM), encompass a typical cell adhesion process. All these ECM molecules along with transcription factors, help in the survival and maintenance of pigmentary cells/melanocytes. Therefore, in this issue, we have tried to compile the literature available on melanocyte detachment/apoptosis in ECM due to the alteration in adhesion molecules and matrix metalloproteinases (MMPs) driven by known/unknown transcription factors.

NRF2, a crucial modulator of skin cells protection against vitiligo, psoriasis, and cancer.

The skin represents a physical barrier between the organism and the environment that has evolved to confer protection against biological, chemical, and physical insults. The inner layer, known as dermis, is constituted by connective tissue and different types of immune cells whereas the outer layer, the epidermis, is composed by different layers of keratinocytes and an abundant number of melanocytes, localized in the stratum basale of the epidermis. Oxidative stress is a common alteration of inflammatory skin disorders such as vitiligo, dermatitis, or psoriasis but can also play a causal role in skin carcinogenesis and tumor progression. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) has emerged as a crucial regulator of cell defense mechanisms activating complex transcriptional programs that facilitate reactive oxygen species detoxification, repair oxidative damage and prevent xenobiotic-induced toxicity. Accumulating evidence suggests that the keratinocytes, melanocytes, and other skin cell types express high levels of NRF2, which is known to play a pivotal role in the skin homeostasis, differentiation, and metabolism during normal and pathologic conditions. In the present review, we summarize the current evidence linking NRF2 to skin pathophysiology and we discuss some recent modulators of NRF2 activity that have shown a therapeutic efficacy in skin protection against tumor initiation and common inflammatory skin conditions such as vitiligo or psoriasis, with a particular emphasis on natural compounds.

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.