serval:BIB_BF783DDCBA05
Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin.
10.1371/journal.pone.0009258
000274654700010
20174635
Dumortier
A.
author
Durham
A.D.
author
Di Piazza
M.
author
Vauclair
S.
author
Koch
U.
author
Ferrand
G.
author
Ferrero
I.
author
Demehri
S.
author
Song
L.L.
author
Farr
A.G.
author
Leonard
W.J.
author
Kopan
R.
author
Miele
L.
author
Hohl
D.
author
Finke
D.
author
Radtke
F.
author
article
2010
PLoS One
1932-6203[electronic], 1932-6203[linking]
journal
5
2
e9258
BACKGROUND: 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. METHODOLOGY AND PRINCIPAL FINDINGS: 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. SIGNIFICANCE: Our data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.
Animals
Cytokines/metabolism
Dermatitis, Atopic/genetics
Dermatitis, Atopic/mortality
Flow Cytometry
Granulocyte Colony-Stimulating Factor/genetics
Granulocyte Colony-Stimulating Factor/metabolism
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Mice, Transgenic
Models, Biological
Myeloproliferative Disorders/genetics
Myeloproliferative Disorders/mortality
Receptor, Notch1/genetics
Receptor, Notch1/physiology
Receptor, Notch2/genetics
Receptor, Notch2/physiology
Receptors, Cytokine/genetics
Receptors, Cytokine/metabolism
Receptors, Notch/genetics
Receptors, Notch/physiology
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction/genetics
Signal Transduction/physiology
Skin/metabolism
Skin/pathology
Survival Analysis
Survival Rate
eng
60_published
true
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