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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

N1N2K5 mice develop a myeloproliferative disorder (MPD).(A) Representative images of spleen and lymph node of control (Ctrl) and N1N2K5 mice showing splenomegaly and lymphadenopathy (n = 12, three individual experiments). (B) HE staining, B220 and CD11b immunofluorescence on spleen sections showing a loss of normal splenic architecture with fibrosis, loss of follicular structures (B220+ B cells) and increase in CD11b+ myeloid cells in N1N2K5 mice (n = 12, three individual experiments). (C) Representative HE staining on liver sections from control and N1N2K5 mice. The liver structure with terminal hepatic venules (v) and portal tracts (T) is changed due to periportal invasion of inflammatory cells and fibrotic reactions in Notch mutant mice (arrows and insert, n = 8, two individual experiments). (D) Representative flow cytometric analysis of splenic myeloid and B cells showing a massive increase in myeloid cells (CD11b+Gr-1int) and loss of follicular (B220+CD23+CD21int) and marginal zone B cells (B220+CD23lo/-CD21+) in N1N2K5 mice. (E) Representative cytometric analysis of bone marrow myeloid and B cells showing an increase in myeloid (CD11b+Gr-1int) and a block of B cell development at the pre-pro B stage (B220+CD43+). Numbers indicate the percentage of cells in each gate. Results are representative of n = 12 per sample group of three individual experiments. [Scale bars: 50 µm].
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pone-0009258-g004: N1N2K5 mice develop a myeloproliferative disorder (MPD).(A) Representative images of spleen and lymph node of control (Ctrl) and N1N2K5 mice showing splenomegaly and lymphadenopathy (n = 12, three individual experiments). (B) HE staining, B220 and CD11b immunofluorescence on spleen sections showing a loss of normal splenic architecture with fibrosis, loss of follicular structures (B220+ B cells) and increase in CD11b+ myeloid cells in N1N2K5 mice (n = 12, three individual experiments). (C) Representative HE staining on liver sections from control and N1N2K5 mice. The liver structure with terminal hepatic venules (v) and portal tracts (T) is changed due to periportal invasion of inflammatory cells and fibrotic reactions in Notch mutant mice (arrows and insert, n = 8, two individual experiments). (D) Representative flow cytometric analysis of splenic myeloid and B cells showing a massive increase in myeloid cells (CD11b+Gr-1int) and loss of follicular (B220+CD23+CD21int) and marginal zone B cells (B220+CD23lo/-CD21+) in N1N2K5 mice. (E) Representative cytometric analysis of bone marrow myeloid and B cells showing an increase in myeloid (CD11b+Gr-1int) and a block of B cell development at the pre-pro B stage (B220+CD43+). Numbers indicate the percentage of cells in each gate. Results are representative of n = 12 per sample group of three individual experiments. [Scale bars: 50 µm].

Mentions: Despite the fact that decreased Notch receptor expression is found in both AD and squamous cell carcinoma (SCC) patients [25], AD patients do not seem to have an increased risk of developing skin malignancies [26]. In contrast, they have an increased probability of developing hematopoietic malignancies and this risk seems to correlate with the severity of AD [27], [28], [29]. Interestingly, autopsy of N1N2K5 and RBP-JK5 mice revealed the development of an apparent myeloproliferative disorder (MPD), which may account for their early death. N1N2K5 and RBP-JK5 mice developed splenomegaly, as well as lymphadenopathy (Figure 4A). This was characterized by a 2-3 fold increase in absolute cell numbers of splenocytes and lymph node cells (Figure S5). Histological and immunohistochemical analysis of the spleen revealed loss of the red and white pulp, splenic fibrosis, loss of B cell follicles and an increase in myeloid cells (Figure 4B), as well as periportal inflammatory infiltrations in the liver (Figure 4C). Flow cytometric (FC) analysis of splenocytes derived from control and N1N2K5 mice confirmed the immunohistochemistry and showed a dramatic increase, in relative percentages and absolute numbers, of mature and immature granulocytes (CD11b+Gr-1+ and CD11b+Gr-1lo/int), and a nearly complete loss of splenic follicular (B220+CD23+CD21int) and marginal zone (B220+CD23lo/intCD21+) B cells (Figure 4D, Figure S5). Further analysis of the BM showed decreased absolute cellularity, revealed an accumulation of immature granulocytes (CD11b+Gr-1lo/int) and a block in B cell development at the (B220+CD43+) pre-pro B cell stage (Figure 4E). Cell cycle analysis also showed increased cycling activity of the granulocytic cell population in the spleen of N1N2K5 and RBP-JK5 mice (data not shown). Taken together, these data strongly suggest that epidermal-specific loss of Notch signaling results in a MPD.


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)

N1N2K5 mice develop a myeloproliferative disorder (MPD).(A) Representative images of spleen and lymph node of control (Ctrl) and N1N2K5 mice showing splenomegaly and lymphadenopathy (n = 12, three individual experiments). (B) HE staining, B220 and CD11b immunofluorescence on spleen sections showing a loss of normal splenic architecture with fibrosis, loss of follicular structures (B220+ B cells) and increase in CD11b+ myeloid cells in N1N2K5 mice (n = 12, three individual experiments). (C) Representative HE staining on liver sections from control and N1N2K5 mice. The liver structure with terminal hepatic venules (v) and portal tracts (T) is changed due to periportal invasion of inflammatory cells and fibrotic reactions in Notch mutant mice (arrows and insert, n = 8, two individual experiments). (D) Representative flow cytometric analysis of splenic myeloid and B cells showing a massive increase in myeloid cells (CD11b+Gr-1int) and loss of follicular (B220+CD23+CD21int) and marginal zone B cells (B220+CD23lo/-CD21+) in N1N2K5 mice. (E) Representative cytometric analysis of bone marrow myeloid and B cells showing an increase in myeloid (CD11b+Gr-1int) and a block of B cell development at the pre-pro B stage (B220+CD43+). Numbers indicate the percentage of cells in each gate. Results are representative of n = 12 per sample group of three individual experiments. [Scale bars: 50 µm].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0009258-g004: N1N2K5 mice develop a myeloproliferative disorder (MPD).(A) Representative images of spleen and lymph node of control (Ctrl) and N1N2K5 mice showing splenomegaly and lymphadenopathy (n = 12, three individual experiments). (B) HE staining, B220 and CD11b immunofluorescence on spleen sections showing a loss of normal splenic architecture with fibrosis, loss of follicular structures (B220+ B cells) and increase in CD11b+ myeloid cells in N1N2K5 mice (n = 12, three individual experiments). (C) Representative HE staining on liver sections from control and N1N2K5 mice. The liver structure with terminal hepatic venules (v) and portal tracts (T) is changed due to periportal invasion of inflammatory cells and fibrotic reactions in Notch mutant mice (arrows and insert, n = 8, two individual experiments). (D) Representative flow cytometric analysis of splenic myeloid and B cells showing a massive increase in myeloid cells (CD11b+Gr-1int) and loss of follicular (B220+CD23+CD21int) and marginal zone B cells (B220+CD23lo/-CD21+) in N1N2K5 mice. (E) Representative cytometric analysis of bone marrow myeloid and B cells showing an increase in myeloid (CD11b+Gr-1int) and a block of B cell development at the pre-pro B stage (B220+CD43+). Numbers indicate the percentage of cells in each gate. Results are representative of n = 12 per sample group of three individual experiments. [Scale bars: 50 µm].
Mentions: Despite the fact that decreased Notch receptor expression is found in both AD and squamous cell carcinoma (SCC) patients [25], AD patients do not seem to have an increased risk of developing skin malignancies [26]. In contrast, they have an increased probability of developing hematopoietic malignancies and this risk seems to correlate with the severity of AD [27], [28], [29]. Interestingly, autopsy of N1N2K5 and RBP-JK5 mice revealed the development of an apparent myeloproliferative disorder (MPD), which may account for their early death. N1N2K5 and RBP-JK5 mice developed splenomegaly, as well as lymphadenopathy (Figure 4A). This was characterized by a 2-3 fold increase in absolute cell numbers of splenocytes and lymph node cells (Figure S5). Histological and immunohistochemical analysis of the spleen revealed loss of the red and white pulp, splenic fibrosis, loss of B cell follicles and an increase in myeloid cells (Figure 4B), as well as periportal inflammatory infiltrations in the liver (Figure 4C). Flow cytometric (FC) analysis of splenocytes derived from control and N1N2K5 mice confirmed the immunohistochemistry and showed a dramatic increase, in relative percentages and absolute numbers, of mature and immature granulocytes (CD11b+Gr-1+ and CD11b+Gr-1lo/int), and a nearly complete loss of splenic follicular (B220+CD23+CD21int) and marginal zone (B220+CD23lo/intCD21+) B cells (Figure 4D, Figure S5). Further analysis of the BM showed decreased absolute cellularity, revealed an accumulation of immature granulocytes (CD11b+Gr-1lo/int) and a block in B cell development at the (B220+CD43+) pre-pro B cell stage (Figure 4E). Cell cycle analysis also showed increased cycling activity of the granulocytic cell population in the spleen of N1N2K5 and RBP-JK5 mice (data not shown). Taken together, these data strongly suggest that epidermal-specific loss of Notch signaling results in a MPD.

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