A direct link between MITF, innate immunity, and hair graying.
A direct link between MITF, innate immunity, and hair graying.
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DOI：
10.1371/journal.pbio.2003648
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发表时间：
2018-05
期刊：
影响因子：
9.8
通讯作者：
Pavan WJ
中科院分区：
文献类型：
--
作者：
Harris ML;Fufa TD;Palmer JW;Joshi SS;Larson DM;Incao A;Gildea DE;Trivedi NS;Lee AN;Day CP;Michael HT;Hornyak TJ;Merlino G;NISC Comparative Sequencing Program;Pavan WJ
黑素细胞干细胞(McSCs)和小鼠头发白化模型是揭示干细胞自我更新和再生组织维持机制的有用系统。在评估影响MCSC维持的遗传变异方面，我们先前发现，与黑素生成相关的转录因子MITF的杂合性加剧了MCSC的分化和易患此表型的小鼠的毛发变白。基于Mitfmi-vga9/+小鼠的转录组和分子分析，我们报道了MITF在调节系统天然免疫基因表达中的新作用。我们还证明了病毒模拟聚(I：C)足以暴露头发变白的遗传易感性。这些观察指向了一种关键的天然免疫抑制因子，即天然免疫失调对色素沉着的影响，这两者都可能与自身免疫性脱色疾病白癜风有关。头发一生中的色素沉着取决于毛囊中的黑素细胞干细胞。随着旧头发的脱落和新头发的生长，黑素细胞干细胞成为黑素细胞的储存库，黑素细胞产生的色素赋予头发可见的颜色。这些干细胞的丧失会导致无色或灰色毛发的生长。评估头发变白的小鼠模型可以揭示黑素细胞干细胞生物学的关键方面。利用这种方法，我们发现了与黑素发生相关的转录因子MITF在抑制黑素细胞系细胞内先天免疫基因表达方面的新作用。这种抑制的重要性在有头发变白倾向的动物身上得到了揭示。在这些动物中，通过遗传机制或通过暴露在病毒模拟环境中，人为提高先天免疫反应，导致显著的黑素细胞和黑素细胞干细胞丢失，并导致灰发数量的增加。这些观察结果突显了先天免疫激活对黑素细胞和黑素细胞干细胞生理的负面影响，并表明病毒感染和头发变白之间存在联系。
Melanocyte stem cells (McSCs) and mouse models of hair graying serve as useful systems to uncover mechanisms involved in stem cell self-renewal and the maintenance of regenerating tissues. Interested in assessing genetic variants that influence McSC maintenance, we found previously that heterozygosity for the melanogenesis associated transcription factor, Mitf, exacerbates McSC differentiation and hair graying in mice that are predisposed for this phenotype. Based on transcriptome and molecular analyses of Mitfmi-vga9/+ mice, we report a novel role for MITF in the regulation of systemic innate immune gene expression. We also demonstrate that the viral mimic poly(I:C) is sufficient to expose genetic susceptibility to hair graying. These observations point to a critical suppressor of innate immunity, the consequences of innate immune dysregulation on pigmentation, both of which may have implications in the autoimmune, depigmenting disease, vitiligo. Hair pigmentation over the course of a lifetime depends on melanocyte stem cells that reside in the hair follicle. As old hairs fall out and new hairs grow in, melanocyte stem cells serve as a reservoir for the melanocytes that produce the pigment that gives hair its visible color. The loss of these stem cells leads to the growth of nonpigmented, or gray, hairs. Evaluating mouse models of hair graying can reveal key aspects of melanocyte stem cell biology. Using this approach, we discovered a novel role for the melanogenesis associated transcription factor, MITF, in repressing the expression of innate immune genes within cells of the melanocyte lineage. The importance of this repression is revealed in animals that have a predisposition for hair graying. In these animals, artificial elevation of the innate immune response, either through a genetic mechanism or via exposure to viral mimic, results in significant melanocyte and melanocyte stem cell loss and leads to the production of an increased number of gray hairs. These observations highlight the negative effects of innate immune activation on melanocyte and melanocyte stem cell physiology and suggest a connection between viral infection and hair graying.
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影响因子：
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