Notch-Deficient Skin Induces a Lethal Systemic B-Lymphoproliferative Disorder by Secreting TSLP, a Sentinel for Epidermal Integrity

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Abstract
Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j–dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations. Skin is the largest organ of the body, forming an elaborate barrier that prevents water loss and protects the internal environment from outside invaders. When this barrier is compromised, keratinocytes, keratin-producing epidermal cells, alert and recruit the immune cells to the site of the breach as part of an adaptive defense mechanism. However, chronic activation of such an “alarm” could have undesired consequences. Using genetic engineering to progressively remove components of Notch signaling from mouse skin in utero resulted in chronic skin-barrier defects, mimicking a form of human skin disease called atopic dermatitis. Surprisingly, we discovered that a persistent alarm signal in newborns triggered a systemic B-lymphoproliferative disorder, which precisely mirrored the degree of skin defect and was lethal in its extreme form. This alarm signal, in the form of a cytokine called thymic stromal lymphopoietin, was produced by Notch-deficient keratinocytes that failed to form a competent skin barrier. Therefore, we uncovered a long-range proliferative effect on fetal pre-B cells in vivo that is induced by injured skin and mediated by thymic stromal lymphopoietin. These findings highlight the central role that skin-derived factors can play in initiating systemic diseases with skin involvement.