期刊
PLOS BIOLOGY
卷 6, 期 5, 页码 992-1005出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.0060123
关键词
-
资金
- NIAMS NIH HHS [R01 AR049269-03, R01 AR049269] Funding Source: Medline
- NICHD NIH HHS [R01 HD044056-05, R01 HD044056, HD044056-01] Funding Source: Medline
- NIDDK NIH HHS [DK066408, R01 DK066408] Funding Source: Medline
- NIGMS NIH HHS [R01 GM055479, GM55479-10] Funding Source: Medline
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据