Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity

PLoS Biol. 2008 May 27;6(5):e123. doi: 10.1371/journal.pbio.0060123.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / deficiency
  • Animals
  • Animals, Newborn
  • B-Lymphocytes* / cytology
  • Cell Proliferation
  • Cytokines / metabolism*
  • Epidermis / enzymology
  • Epidermis / metabolism
  • Epidermis / pathology*
  • Female
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Keratinocytes / metabolism
  • Leukocyte Count
  • Longevity
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / physiopathology*
  • Mice
  • Pregnancy
  • Receptors, Notch / deficiency*
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Survival Analysis
  • Time Factors

Substances

  • Cytokines
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Receptors, Notch
  • Amyloid Precursor Protein Secretases
  • thymic stromal lymphopoietin