Atopic Dermatitis-Like Disease and Associated Lethal Myeloproliferative Disorder Arise from Loss of Notch Signaling in the Murine Skin

Abstract

BackgroundThe 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 FindingsTo 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.SignificanceOur data demonstrate a critical role for Notch in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the hematopoietic system.

Development and Homeostasis of the Skin Epidermis

“…In addition to cancer, Notch signaling controls inflammatory responses. Notch deficiency during embryonic development leads to non-cell-autonomous B-cell lymphoproliferative disorder, whereas in adult mice it results in severe atopic dermatitis because of elevated levels of thymic stromal lymphopoietin, possibly because of impaired barrier formation, consistent with the finding that patients suffering from atopic dermatitis have reduced Notch expression in the skin (Dumortier et al 2010). The elevated levels of thymic stromal lymphopoietin may subsequently act systemically and lead to allergic asthma development, explaining the elevated cases of asthma within atopic dermatitis patients (Demehri et al 2009).…”

New insights in the pathogenesis of atopic dermatitis

“…Epidermal expression of IL-4 and IL-17 was also found to be increased in ADAM17-deleted mice (31). The absence of ADAM17 in the mice results in a reduction of epidermal growth factor receptor and Notch signaling, which lead to increased expression of IL-33, and AP-1, TSLP, IL-4, and IL-13, respectively (30)(31)(32). However, increased expression of IL-17 is not a prominent feature of human AD lesions, but it is a characteristic of psoriatic lesions (33).…”

Keratin 79 identifies a novel population of migratory epithelial cells that initiates hair canal morphogenesis and regeneration

“…Disruption of Notch activity in the skin, either by genetic ablation of Notch pathway components or by expression of dominant-negative GFP-tagged mastermind-like 1 (dnMAML), can induce widespread cyst formation (Blanpain et al, 2006;Demehri and Kopan, 2009;Dumortier et al, 2010;Pan et al, 2004;Proweller et al, 2006;Vauclair et al, 2005;Yamamoto et al, 2003). To determine whether Notch is required to maintain the INF, we generated mice expressing Lrig1-Cre ERT2 and a Cre-inducible dnMAML cassette under the control of the ROSA26 promoter (Lrig1;dnMAML).…”