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

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 - PLoS ONE (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL SV ISREC), Lausanne, Switzerland.

ABSTRACT

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.

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Related in: MedlinePlus

Notch receptor expression is down regulated in skin samples of AD patients.H/E staining of representative skin sections derived from (A) human control skin (n = 9) and lesional sites from the following human skin disorders: (D) atopic dermatitis (n = 9), (G) psoriasis (n = 4), and (J) lichen planus (n = 4). (B, E, F, H, I, K and L) show panNotch staining using a DL4-IgG fusion protein while (C) shows control staining with a hIgG isotype control antibody. Nuclei are counterstained with DAPI. (E-F) shows down regulation of Notch receptor expression in skin sections from two different AD patients, while (H-I) reveals the presence of Notch expression on sections from two psoriasis patients and (K-L) from two patients suffering from lichen planus. [Scale bars: 50 µm].
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pone-0009258-g003: Notch receptor expression is down regulated in skin samples of AD patients.H/E staining of representative skin sections derived from (A) human control skin (n = 9) and lesional sites from the following human skin disorders: (D) atopic dermatitis (n = 9), (G) psoriasis (n = 4), and (J) lichen planus (n = 4). (B, E, F, H, I, K and L) show panNotch staining using a DL4-IgG fusion protein while (C) shows control staining with a hIgG isotype control antibody. Nuclei are counterstained with DAPI. (E-F) shows down regulation of Notch receptor expression in skin sections from two different AD patients, while (H-I) reveals the presence of Notch expression on sections from two psoriasis patients and (K-L) from two patients suffering from lichen planus. [Scale bars: 50 µm].

Mentions: Since loss of Notch signaling and TSLP expression are linked in mouse skin, we assessed a possible role for Notch in the etiology of AD in humans. Therefore, we analyzed the presence of Notch receptors with a tagged ligand (DL4-FC) [17] that recognizes presumably all four Notch paralogs in affected areas of biopsy samples from AD patients (n = 9) compared to control patients (n = 9). Notch receptor expression is confined to the suprabasal cell layer of unaffected skin samples (Figure 3A-C). In contrast, Notch receptor protein expression was greatly reduced or even no longer detectable in lesional skin in 7 out of 9 AD patients (Figure 3D-F). As Notch has been shown to induce early differentiation events and has been linked to cell cycle withdrawal, it is possible that diminished Notch receptor expression is common to many hyperproliferative skin disorders rather then specific to AD. We therefore analyzed biopsy samples from psoriasis (n = 4) and lichen planus patients (n = 4). Patient tissue samples from both of these hyperproliferative skin disorders showed a strong presence of Notch receptors (Figure 3G-L) indicating that Notch receptor regulation and signaling is closely linked to AD and not to the other skin disorders tested.


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

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 - PLoS ONE (2010)

Notch receptor expression is down regulated in skin samples of AD patients.H/E staining of representative skin sections derived from (A) human control skin (n = 9) and lesional sites from the following human skin disorders: (D) atopic dermatitis (n = 9), (G) psoriasis (n = 4), and (J) lichen planus (n = 4). (B, E, F, H, I, K and L) show panNotch staining using a DL4-IgG fusion protein while (C) shows control staining with a hIgG isotype control antibody. Nuclei are counterstained with DAPI. (E-F) shows down regulation of Notch receptor expression in skin sections from two different AD patients, while (H-I) reveals the presence of Notch expression on sections from two psoriasis patients and (K-L) from two patients suffering from lichen planus. [Scale bars: 50 µm].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2823782&req=5

pone-0009258-g003: Notch receptor expression is down regulated in skin samples of AD patients.H/E staining of representative skin sections derived from (A) human control skin (n = 9) and lesional sites from the following human skin disorders: (D) atopic dermatitis (n = 9), (G) psoriasis (n = 4), and (J) lichen planus (n = 4). (B, E, F, H, I, K and L) show panNotch staining using a DL4-IgG fusion protein while (C) shows control staining with a hIgG isotype control antibody. Nuclei are counterstained with DAPI. (E-F) shows down regulation of Notch receptor expression in skin sections from two different AD patients, while (H-I) reveals the presence of Notch expression on sections from two psoriasis patients and (K-L) from two patients suffering from lichen planus. [Scale bars: 50 µm].
Mentions: Since loss of Notch signaling and TSLP expression are linked in mouse skin, we assessed a possible role for Notch in the etiology of AD in humans. Therefore, we analyzed the presence of Notch receptors with a tagged ligand (DL4-FC) [17] that recognizes presumably all four Notch paralogs in affected areas of biopsy samples from AD patients (n = 9) compared to control patients (n = 9). Notch receptor expression is confined to the suprabasal cell layer of unaffected skin samples (Figure 3A-C). In contrast, Notch receptor protein expression was greatly reduced or even no longer detectable in lesional skin in 7 out of 9 AD patients (Figure 3D-F). As Notch has been shown to induce early differentiation events and has been linked to cell cycle withdrawal, it is possible that diminished Notch receptor expression is common to many hyperproliferative skin disorders rather then specific to AD. We therefore analyzed biopsy samples from psoriasis (n = 4) and lichen planus patients (n = 4). Patient tissue samples from both of these hyperproliferative skin disorders showed a strong presence of Notch receptors (Figure 3G-L) indicating that Notch receptor regulation and signaling is closely linked to AD and not to the other skin disorders tested.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL SV ISREC), Lausanne, Switzerland.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus