Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin.
Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin.
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DOI：
10.1371/journal.pone.0009258
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发表时间：
2010-02-18
期刊：
影响因子：
3.7
通讯作者：
Radtke F
中科院分区：
文献类型：
--
作者：
Dumortier A;Durham AD;Di Piazza M;Vauclair S;Koch U;Ferrand G;Ferrero I;Demehri S;Song LL;Farr AG;Leonard WJ;Kopan R;Miele L;Hohl D;Finke D;Radtke F
Notch通路对于胚胎皮肤发育期间的适当表皮分化是必不可少的。此外，胚胎中Notch信号传导的皮肤特异性损失导致皮肤屏障缺陷伴随B淋巴细胞增生性疾病。然而，人们对出生后Notch信号丢失的后果知之甚少。为了研究Notch信号传导在成年小鼠皮肤中的功能，我们使用了一系列条件性基因靶向小鼠，其允许特异性地在皮肤中失活Notch信号传导途径的几种组分。我们证明，皮肤特异性失活的Notch 1和Notch 2的同时，或RBP-J，诱导特应性皮炎（AD）的严重形式的发展，其特征在于棘层，海绵和角化过度，以及大量的嗜酸性粒细胞和肥大细胞的真皮浸润。同样地，患有AD而非牛皮癣或扁平苔藓的患者在皮肤中具有Notch受体表达的显著降低。角质形成细胞中Notch的缺失诱导胸腺基质淋巴细胞生成素（TSLP）的产生，TSLP是一种与AD发病机制密切相关的细胞因子。AD样相关炎症伴有骨髓增生性疾病（MPD），其特征为骨髓和脾脏中未成熟髓样细胞群增加。移植研究表明，MPD是细胞非自主性的，是由剧烈的微环境改变引起的。遗传学研究表明，G-CSF介导MPD以及骨髓微环境的变化导致骨质减少。我们的数据证明了Notch在抑制角质形成细胞中TSLP产生中的关键作用，从而维持皮肤和造血系统的完整性。
The Notch pathway is essential for proper epidermal differentiation during embryonic skin development. Moreover, skin specific loss of Notch signaling in the embryo results in skin barrier defects accompanied by a B-lymphoproliferative disease. However, much less is known about the consequences of loss of Notch signaling after birth. To study the function of Notch signaling in the skin of adult mice, we made use of a series of conditional gene targeted mice that allow inactivation of several components of the Notch signaling pathway specifically in the skin. We demonstrate that skin-specific inactivation of Notch1 and Notch2 simultaneously, or RBP-J, induces the development of a severe form of atopic dermatitis (AD), characterized by acanthosis, spongiosis and hyperkeratosis, as well as a massive dermal infiltration of eosinophils and mast cells. Likewise, patients suffering from AD, but not psoriasis or lichen planus, have a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP), a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a myeloproliferative disorder (MPD) characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell non-autonomous and caused by dramatic microenvironmental alterations. Genetic studies demontrated that G-CSF mediates the MPD as well as changes in the bone marrow microenvironment leading to osteopenia. Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.
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DOI：
10.1084/jem.20082242
发表时间：
2009-05-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Briot A;Deraison C;Lacroix M;Bonnart C;Robin A;Besson C;Dubus P;Hovnanian A
通讯作者：
Hovnanian A
DOI：
10.1084/jem.20061442
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Radtke F
DOI：
10.1084/jem.20062211
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Allakhverdi Z;Comeau MR;Jessup HK;Yoon BR;Brewer A;Chartier S;Paquette N;Ziegler SF;Sarfati M;Delespesse G
通讯作者：
Delespesse G
影响因子：
16.8
作者：
Holgate, Stephen T.
通讯作者：
Holgate, Stephen T.
影响因子：
14.9
作者：
Indra, AK;Warot, X;Metzger, D
通讯作者：
Metzger, D