The Potential Role of Impaired Notch Signalling in Atopic Dermatitis

Abstract

This review presents recent evidence of impaired Notch signalling in atopic dermatitis (AD), which is proposed to represent the "a-topic" defect linking both epidermal and immunological barrier dysfunctions in AD. AD epidermis exhibits a marked deficiency of Notch receptors. Mouse models with genetically suppressed Notch signalling exhibit dry skin, signs of scratching, skin barrier abnormalities, increased transepidermal water loss and TH2 cell-mediated immunological changes closely resembling human AD. Notch signals are critically involved in the differentiation of regulatory T cells, in the feedback inhibition of activated innate immunity, in late epidermal differentiation associated with filaggrin- and stratum corneum barrier lipid processing. Most importantly, Notch deficiency induces keratinocyte-mediated release of thymic stromal lymphopoietin (TSLP). TSLP promotes TH2 cell-driven immune responses associated with enhanced production of interleukin (IL)-4 and IL-31. Both TSLP and IL-31 stimulate sensory cutaneous neurons involved in the induction of itch. Notably, Notch1 is a repressor of activator protein-1 (AP-1), which is upregulated in AD epidermis. Without Notch-mediated suppression of AP-1 this transcription factor promotes excess expression of TH2 cell-related cytokines. Impaired Notch signalling negatively affects the homeostasis of aquaporin 3 and of the tight junction component claudin-1, thus explains disturbed skin barrier function with increased transepidermal water loss and Staphylococcus aureus colonisation as well as increased cutaneous susceptibility for viral infections. Thus, accumulating evidence links deficient Notch signalling to key pathological features of AD.

The importance of TSLP in allergic disease and its role as a potential therapeutic target

“…One possible mechanism is that TSLP is increased due to skin injury (chronic itch in AD or underlying skin defect) and/or Notch signaling impairment, which is common in AD. Indeed, AD epidermis has a marked deficiency of Notch receptors [99], which has been linked to increased TSLP expression. In a mouse model, Notch signaling defects in keratinocyte cause severe epidermal differentiation defects (dry skin, signs of scratching, skin barrier abnormalities, increased transepidermal water loss) and high systemic levels of TSLP with associated Th2 cell-mediated immunological changes [100].…”

“…In a mouse model, Notch signaling defects in keratinocyte cause severe epidermal differentiation defects (dry skin, signs of scratching, skin barrier abnormalities, increased transepidermal water loss) and high systemic levels of TSLP with associated Th2 cell-mediated immunological changes [100]. In addition, Notch signals are critically involved in the differentiation of Treg cells, in the feedback inhibition of activated innate immunity, and in late epidermal differentiation associated with filaggerin- and stratum corneum barrier lipid processing [99]. Specifically, Notch signaling regulates the homeostasis of aqua-porin 3 and of the tight junction component claudin-1 and Notch1 is a repressor of activator protein-1, which is up-regulated in AD epidermis and leads to increased IL-31 [99].…”

“…In addition, Notch signals are critically involved in the differentiation of Treg cells, in the feedback inhibition of activated innate immunity, and in late epidermal differentiation associated with filaggerin- and stratum corneum barrier lipid processing [99]. Specifically, Notch signaling regulates the homeostasis of aqua-porin 3 and of the tight junction component claudin-1 and Notch1 is a repressor of activator protein-1, which is up-regulated in AD epidermis and leads to increased IL-31 [99]. However, TSLP expression may be due to skin barrier defects that are known to directly induce TSLP [101,102] rather than resulting directly from the loss of keratinocyte-specific Notch [100].…”

Skin Barrier Dysfunction and the Atopic March

“…Other T cell types, notably Th17 and thymus-derived and inducible regulatory T cells, have also been shown to be involved in the pathogenesis of AD, as have cells of the innate immune system [20,21]. More recently, impaired Notch signalling has been appraised as a unifying paradigm linking epidermal barrier defects and immunological abnormalities in AD [22]. Specifically, Notch signalling are involved in the differentiation of regulatory T cells, in the feedback inhibition of activated innate immunity, in epidermal differentiation associated with filaggrin, in stratum corneum barrier lipid processing and in induction of keratinocyte-mediated release of thymic stromal lymphopoietin (TSLP), which promotes Th2 cell-driven immune responses [22].…”

“…Specifically, Notch signalling are involved in the differentiation of regulatory T cells, in the feedback inhibition of activated innate immunity, in epidermal differentiation associated with filaggrin, in stratum corneum barrier lipid processing and in induction of keratinocyte-mediated release of thymic stromal lymphopoietin (TSLP), which promotes Th2 cell-driven immune responses [22]. Also, Notch deficiency affects the homeostasis of aquaporins and specific tight junction components, leading to increased transepidermal water loss (TEWL), Staphylococcus aureus colonization and increased cutaneous susceptibility for viral infections [22].…”