Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of notch signaling in the murine skin

Autor: Alexis Dumortier, Sophie Vauclair, Gisèle Ferrand, Lynda Li Song, Freddy Radtke, Daniela Finke, Matteo Di Piazza, Shadmehr Demehri, Lucio Miele, André-Dante Durham, Isabel Ferrero, Daniel Hohl, Raphael Kopan, Warren J. Leonard, Andrew G. Farr, Ute Koch
Předmět:
Myeloid
Stem-Cells
medicine.medical_treatment
lcsh:Medicine
Human Epithelial-Cells
Expression
Mice
0302 clinical medicine
Granulocyte Colony-Stimulating Factor
Receptor
Notch2
Receptor
Notch1
lcsh:Science
Skin
Mice
Knockout
0303 health sciences
Multidisciplinary
Receptors
Notch
integumentary system
Reverse Transcriptase Polymerase Chain Reaction
Flow Cytometry
Survival Rate
Mouse Keratinocytes
medicine.anatomical_structure
Cytokine
030220 oncology & carcinogenesis
Cytokines
Stem cell
Immunology/Allergy and Hypersensitivity
Signal Transduction
Research Article
Thymic stromal lymphopoietin
Notch signaling pathway
Growth-Factor
Immunoglobulins
Mice
Nude
Mice
Transgenic
Biology
Models
Biological
Dermatitis
Atopic
03 medical and health sciences
Thymic Stromal Lymphopoietin
Psoriasis
medicine
Animals
Humans
Receptors
Cytokine
030304 developmental biology
Myeloproliferative Disorders
lcsh:R
medicine.disease
T-Cell
Survival Analysis
Mice
Inbred C57BL
Transplantation
B-Cell Development
Genetics and Genomics/Disease Models
In-Vitro
Immunology
lcsh:Q
Bone marrow
Dermatology/Atopic Dermatitis and Other Forms of Eczema
Cytokines/metabolism
Dermatitis
Atopic/genetics
Dermatitis
Atopic/mortality
Granulocyte Colony-Stimulating Factor/genetics
Granulocyte Colony-Stimulating Factor/metabolism
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
Signal Transduction/genetics
Signal Transduction/physiology
Skin/metabolism
Skin/pathology
Zdroj: PLoS ONE
PLoS One, vol. 5, no. 2, pp. e9258
PLoS ONE; Vol 5
PLoS ONE, Vol 5, Iss 2, p e9258 (2010)
Popis: 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.
Databáze: OpenAIRE
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