Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin
Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin
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DOI：
10.1073/pnas.0507385102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Chambon, P
中科院分区：
文献类型：
--
作者：
Li, M;Messaddeq, N;Chambon, P
为了研究类维生素A X受体（RXR）在表皮稳态中的作用，我们产生了RXR α β（ep-/-）体细胞突变体，其中RXR α和RXR β在成年小鼠的表皮角质形成细胞中被选择性地消融。这些小鼠发生慢性皮炎，模仿在特应性皮炎（AD）患者中观察到的。此外，它们表现出免疫学异常，包括IgE和IgG的血清水平升高，与血液和组织嗜酸性粒细胞增多症相关，表明RXR的角质形成细胞选择性消融也产生与AD患者中发现的相似的全身综合征。此外，角质形成细胞选择性RXR α β消融突变体皮肤中细胞因子和趋化因子表达增加的特征是辅助性T细胞2型炎症的典型特征，已知其在人类AD发病机制中至关重要。最后，我们证明，胸腺基质淋巴细胞生成素，其表达是快速和强烈诱导的RXR α β消融角质形成细胞，在启动皮肤和全身AD样病变中起着关键作用。
To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXR alpha beta(ep-/-) somatic mutants in which both RXR alpha and RXR beta are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXR alpha beta-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXR alpha beta-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies.