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Medicinal Research Reviews Mar 2021Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation.... (Review)
Review
Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation. Genome-wide associated studies have identified single-nucleotide polymorphisms in a panel of susceptible loci as risk factors in melanocyte death. But vitiligo onset can't be solely attributed to a susceptive genetic background. Oxidative stress triggered by elevated levels of reactive oxygen species accounts for melanocytic molecular and organelle dysfunction, a minority of melanocyte demise, and melanocyte-specific antigens exposure. Of note, the self-responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo. The aberrantly heightened innate immunity, type-1-skewed T helper, and incompetent regulatory T cells tip the balance toward autoreaction and CD8 cytotoxic T lymphocytes finally execute the killing of melanocytes, possibly alarmed by resident memory T cells. In addition to the well-established apoptosis and necrosis, we discuss several death modalities like oxeiptosis, ferroptosis, and necroptosis that are probably employed in melanocyte destruction. This review focuses on the various mechanisms of melanocytic death in vitiligo pathogenesis to demonstrate a panorama of that. We hope to provide new insights into vitiligo pathogenesis and treatment strategies by the review.
Topics: Apoptosis; CD8-Positive T-Lymphocytes; Humans; Melanocytes; Oxidative Stress; Vitiligo
PubMed: 33200838
DOI: 10.1002/med.21754 -
Anais Brasileiros de Dermatologia 2022Vitiligo is a complex disease whose pathogenesis results from the interaction of genetic components, metabolic factors linked to cellular oxidative stress, melanocyte... (Review)
Review
Vitiligo is a complex disease whose pathogenesis results from the interaction of genetic components, metabolic factors linked to cellular oxidative stress, melanocyte adhesion to the epithelium, and immunity (innate and adaptive), which culminate in aggression against melanocytes. In vitiligo, melanocytes are more sensitive to oxidative damage, leading to the increased expression of proinflammatory proteins such as HSP70. The lower expression of epithelial adhesion molecules, such as DDR1 and E-cadherin, facilitates damage to melanocytes and exposure of antigens that favor autoimmunity. Activation of the type 1-IFN pathway perpetuates the direct action of CD8+ cells against melanocytes, facilitated by regulatory T-cell dysfunction. The identification of several genes involved in these processes sets the stage for disease development and maintenance. However, the relationship of vitiligo with environmental factors, psychological stress, comorbidities, and the elements that define individual susceptibility to the disease are a challenge to the integration of theories related to its pathogenesis.
Topics: Autoimmunity; Humans; Melanocytes; Oxidative Stress; Vitiligo
PubMed: 35643735
DOI: 10.1016/j.abd.2021.09.008 -
Genes & Development Aug 2019All transcription factors are equal, but some are more equal than others. In the 25 yr since the gene encoding the microphthalmia-associated transcription factor (MITF)... (Review)
Review
All transcription factors are equal, but some are more equal than others. In the 25 yr since the gene encoding the microphthalmia-associated transcription factor (MITF) was first isolated, MITF has emerged as a key coordinator of many aspects of melanocyte and melanoma biology. Like all transcription factors, MITF binds to specific DNA sequences and up-regulates or down-regulates its target genes. What marks MITF as being remarkable among its peers is the sheer range of biological processes that it appears to coordinate. These include cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair. In this article we present our current understanding of MITF's role and regulation in development and disease, as well as those of the MITF-related factors TFEB and TFE3, and highlight key areas where our knowledge of MITF regulation and function is limited.
Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Gene Expression Regulation, Neoplastic; Genome; Humans; Melanocytes; Melanoma; Microphthalmia-Associated Transcription Factor; Protein Binding; Protein Isoforms
PubMed: 31123060
DOI: 10.1101/gad.324657.119 -
Frontiers in Immunology 2021Vitiligo is a disease of the skin characterized by the appearance of white spots. Significant progress has been made in understanding vitiligo pathogenesis over the past... (Review)
Review
Vitiligo is a disease of the skin characterized by the appearance of white spots. Significant progress has been made in understanding vitiligo pathogenesis over the past 30 years, but only through perseverance, collaboration, and open-minded discussion. Early hypotheses considered roles for innervation, microvascular anomalies, oxidative stress, defects in melanocyte adhesion, autoimmunity, somatic mosaicism, and genetics. Because theories about pathogenesis drive experimental design, focus, and even therapeutic approach, it is important to consider their impact on our current understanding about vitiligo. Animal models allow researchers to perform mechanistic studies, and the development of improved patient sample collection methods provides a platform for translational studies in vitiligo that can also be applied to understand other autoimmune diseases that are more difficult to study in human samples. Here we discuss the history of vitiligo translational research, recent advances, and their implications for new treatment approaches.
Topics: Animals; Autoimmunity; Dermatologic Agents; Disease Models, Animal; Genetic Testing; Humans; Melanocytes; Oxidative Stress; Phenotype; Skin; Skin Pigmentation; Translational Research, Biomedical; Vitiligo
PubMed: 33737930
DOI: 10.3389/fimmu.2021.624517 -
Frontiers in Immunology 2022Vitiligo is a common depigmenting skin disorder characterized by the selective loss of melanocytes. Autoimmunity, genetic, environmental, and biochemical etiology have... (Review)
Review
Vitiligo is a common depigmenting skin disorder characterized by the selective loss of melanocytes. Autoimmunity, genetic, environmental, and biochemical etiology have been proposed in vitiligo pathogenesis. However, the exact molecular mechanisms of vitiligo development and progression are unclear, particularly for immunometabolism. Sporadic studies have suggested mitochondrial dysfunction, enhanced oxidative stress, and specific defects in other metabolic pathways can promote dysregulation of innate and adaptive immune responses in vitiligo. These abnormalities appear to be driven by genetic and epigenetic factors modulated by stochastic events. In addition, glucose and lipid abnormalities in metabolism have been associated with vitiligo. Specific skin cell populations are also involved in the critical role of dysregulation of metabolic pathways, including melanocytes, keratinocytes, and tissue-resident memory T cells in vitiligo pathogenesis. Novel therapeutic treatments are also raised based on the abnormalities of immunometabolism. This review summarizes the current knowledge on immunometabolism reprogramming in the pathogenesis of vitiligo and novel treatment options.
Topics: Humans; Vitiligo; Melanocytes; Oxidative Stress; Skin; Autoimmunity
PubMed: 36439174
DOI: 10.3389/fimmu.2022.1055958 -
International Journal of Molecular... Mar 2023Vitiligo is an acquired hypopigmentation of the skin due to a progressive selective loss of melanocytes; it has a prevalence of 1-2% and appears as rounded,... (Review)
Review
Vitiligo is an acquired hypopigmentation of the skin due to a progressive selective loss of melanocytes; it has a prevalence of 1-2% and appears as rounded, well-demarcated white macules. The etiopathology of the disease has not been well defined, but multiple factors contribute to melanocyte loss: metabolic abnormalities, oxidative stress, inflammation, and autoimmunity. Therefore, a convergence theory was proposed that combines all existing theories into a comprehensive one in which several mechanisms contribute to the reduction of melanocyte viability. In addition, increasingly in-depth knowledge about the disease's pathogenetic processes has enabled the development of increasingly targeted therapeutic strategies with high efficacy and fewer side effects. The aim of this paper is, by conducting a narrative review of the literature, to analyze the pathogenesis of vitiligo and the most recent treatments available for this condition.
Topics: Humans; Vitiligo; Hypopigmentation; Melanocytes; Skin; Oxidative Stress
PubMed: 36902341
DOI: 10.3390/ijms24054910 -
Nature Apr 2023For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations, which leads to hair greying in most humans and mice....
For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations, which leads to hair greying in most humans and mice. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.
Topics: Animals; Humans; Mice; Hair Follicle; Melanocytes; Stem Cells; Cell Dedifferentiation; Stem Cell Niche; Cellular Microenvironment; Cell Lineage; Aging; Homeostasis; Hair Color
PubMed: 37076619
DOI: 10.1038/s41586-023-05960-6 -
Nature Jan 2020Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs), but so far there has been little scientific...
Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs), but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.
Topics: Adrenal Glands; Adrenalectomy; Animals; Autonomic Pathways; Cell Proliferation; Cells, Cultured; Denervation; Female; Hair Color; Humans; Male; Melanocytes; Mice; Norepinephrine; Psychological Trauma; Receptors, Adrenergic, beta-2; Stem Cell Niche; Stem Cells; Stress, Psychological; Sympathetic Nervous System
PubMed: 31969699
DOI: 10.1038/s41586-020-1935-3 -
Experimental Dermatology Apr 2021In the light of substantial discoveries in epithelial and hair pigmentation pathophysiology, this review summarizes the current understanding of skin pigmentation... (Review)
Review
In the light of substantial discoveries in epithelial and hair pigmentation pathophysiology, this review summarizes the current understanding of skin pigmentation mechanisms. Melanocytes are pigment-producing cells, and their key regulating transcription factor is the melanocyte-specific microphthalmia-associated transcription factor (m-MITF). Ultraviolet (UV) radiation is a unique modulator of skin pigmentation influencing tanning pathways. The delayed tanning pathway occurs as UVB produces keratinocyte DNA damage, causing p53-mediated expression of the pro-opiomelanocortin (POMC) gene that is processed to release α-melanocyte-stimulating hormone (α-MSH). α-MSH stimulates the melanocortin 1 receptor (MC1R) on melanocytes, leading to m-MITF expression and melanogenesis. POMC cleavage also releases β-endorphin, which creates a neuroendocrine pathway that promotes UV-seeking behaviours. Mutations along the tanning pathway can affect pigmentation and increase the risk of skin malignancies. MC1R variants have received considerable attention, yet the allele is highly polymorphic with varied phenotypes. Vitiligo presents with depigmented skin lesions due to autoimmune destruction of melanocytes. UVB phototherapy stimulates melanocyte stem cells in the hair bulge to undergo differentiation and upwards migration resulting in perifollicular repigmentation of vitiliginous lesions, which is under sophisticated signalling control. Melanocyte stem cells, normally quiescent, undergo cyclic activation/differentiation and downward migration with the hair cycle, providing pigment to hair follicles. Physiological hair greying results from progressive loss of melanocyte stem cells and can be accelerated by acute stress-induced, sympathetic driven hyperproliferation of the melanocyte stem cells. Ultimately, by reviewing the pathways governing epithelial and follicular pigmentation, numerous areas of future research and potential points of intervention are highlighted.
Topics: Hair Follicle; Humans; Melanocytes; Microphthalmia-Associated Transcription Factor; Skin Pigmentation; Stem Cells; Ultraviolet Rays; Ultraviolet Therapy; Vitiligo
PubMed: 33320376
DOI: 10.1111/exd.14260 -
Molecular Medicine Reports Mar 2020The occurrence of hyperpigmentation or hypopigmentation after inflammation is a common condition in dermatology and cosmetology. Since the exact mechanism of its... (Review)
Review
The occurrence of hyperpigmentation or hypopigmentation after inflammation is a common condition in dermatology and cosmetology. Since the exact mechanism of its occurrence is not yet known, prevention and treatment are troublesome. Previous studies have confirmed that α‑melanocyte‑stimulating hormone, stem cell factor and other factors can promote melanogenesis‑related gene expression through the activation of signaling pathways. Recent studies have revealed that a variety of inflammatory mediators can also participate in the regulation of melanogenesis in melanocytes. In this review, we summarized that interleukin‑18, interleukin‑33, granulocyte‑macrophage colony stimulating factor, interferon‑γ, prostaglandin E2 have the effect of promoting melanogenesis, while interleukin‑1, interleukin‑4, interleukin‑6, interleukin‑17 and tumor necrosis factor can inhibit melanogenesis. Further studies have found that these inflammatory factors may activate or inhibit melanogenesis‑related signaling pathways (such as protein kinase A and mitogen activated protein kinase) by binding to corresponding receptors, thereby promoting or inhibiting the expression of melanogenesis‑related genes and regulating skin pigmentation processes. This suggests that the development of drugs or treatment methods from the perspective of regulating inflammation can provide new ideas and new targets for the treatment of pigmented dermatosis. This review outlines the current understanding of the inflammation factors' roles in melanogenesis.
Topics: Cytokines; Dinoprostone; Humans; Inflammation; Melanins; Melanocytes; Pigmentation Disorders; Signal Transduction; Skin Pigmentation; alpha-MSH
PubMed: 32016458
DOI: 10.3892/mmr.2020.10950