Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity.
Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity.
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DOI：
10.1371/journal.pbio.0060123
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发表时间：
2008-05-27
期刊：
影响因子：
9.8
通讯作者：
Kopan R
中科院分区：
文献类型：
--
作者：
Demehri S;Liu Z;Lee J;Lin MH;Crosby SD;Roberts CJ;Grigsby PW;Miner JH;Farr AG;Kopan R
表皮角质形成细胞形成高度组织化的复层上皮，并与真皮和造血细胞一起维持有效的屏障功能。 Notch 信号通路是表皮完整性的关键调节因子。在这里，我们发现角质形成细胞特异性删除总 Notch 信号传导会引发严重的全身性 B 淋巴细胞增殖性疾病，从而导致死亡。 RBP-j 是 Notch 的 DNA 结合伴侣，但 RBP-j 依赖性和独立的 Notch 信号传导对于适当的表皮分化和脂质沉积都是必需的。这两条途径的丧失导致皮肤分化/屏障形成的持续缺陷。作为回应，高水平的胸腺基质淋巴细胞生成素（TSLP）被Notch缺陷的角质形成细胞释放到体循环中，这些角质形成细胞从子宫内开始就无法分化。新生儿造血过程中暴露于高 TSLP 水平会导致外周前和未成熟 B 淋巴细胞急剧扩增，引起与主要器官浸润和随后死亡相关的 B 淋巴细胞增殖性疾病，这是 TSLP 的一种以前未被认识到的全身效应。这些观察结果表明，局部皮肤扰动可以引发致命的全身性疾病，并对具有皮肤表现的多种体液和自身免疫性疾病具有重要影响。皮肤是身体最大的器官，形成一个复杂的屏障，防止水分流失并保护内部环境免受外界入侵。当这一屏障受到损害时，角质形成细胞（产生角蛋白的表皮细胞）会发出警报，并将免疫细胞招募到突破部位，作为适应性防御机制的一部分。然而，这种“警报”的长期激活可能会产生不良后果。使用基因工程逐步去除子宫内小鼠皮肤中的 Notch 信号成分，导致慢性皮肤屏障缺陷，类似于一种称为特应性皮炎的人类皮肤病。令人惊讶的是，我们发现新生儿持续发出的警报信号会引发全身性 B 淋巴细胞增殖性疾病，这种疾病恰好反映了皮肤缺损的程度，极端情况下是致命的。这种警报信号以一种称为胸腺基质淋巴细胞生成素的细胞因子的形式存在，是由Notch缺陷的角质形成细胞产生的，这些角质形成细胞无法形成有效的皮肤屏障。因此，我们发现了由受损皮肤诱导并由胸腺基质淋巴细胞生成素介导的对胎儿前 B 细胞体内的长期增殖作用。这些发现强调了皮肤源性因子在引发皮肤受累的全身性疾病中发挥的核心作用。皮肤源性因子在引发致命的全身性疾病中起主导作用。目前的研究结果表明，Notch 缺陷的皮肤对造血产生了新的影响，其中角质形成细胞衍生的细胞因子的独特生物学特性导致了严重的新生儿血液疾病。
Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j–dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations. Skin is the largest organ of the body, forming an elaborate barrier that prevents water loss and protects the internal environment from outside invaders. When this barrier is compromised, keratinocytes, keratin-producing epidermal cells, alert and recruit the immune cells to the site of the breach as part of an adaptive defense mechanism. However, chronic activation of such an “alarm” could have undesired consequences. Using genetic engineering to progressively remove components of Notch signaling from mouse skin in utero resulted in chronic skin-barrier defects, mimicking a form of human skin disease called atopic dermatitis. Surprisingly, we discovered that a persistent alarm signal in newborns triggered a systemic B-lymphoproliferative disorder, which precisely mirrored the degree of skin defect and was lethal in its extreme form. This alarm signal, in the form of a cytokine called thymic stromal lymphopoietin, was produced by Notch-deficient keratinocytes that failed to form a competent skin barrier. Therefore, we uncovered a long-range proliferative effect on fetal pre-B cells in vivo that is induced by injured skin and mediated by thymic stromal lymphopoietin. These findings highlight the central role that skin-derived factors can play in initiating systemic diseases with skin involvement. A skin-derived factor plays a lead role in initiating a lethal systemic disease. The current findings point to a novel impact of Notch-deficient skin on hematopoiesis, where unique biology of a keratinocyte-derived cytokine contributes to a severe neonatal blood disease.
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DOI：
10.1084/jem.20062211
发表时间：
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期刊：
The Journal of experimental medicine
影响因子：
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2006-02-20
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