Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity.
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.
Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America. demehris@msnotes.wustl.edu
Shadmehr
S
Demehri
Zhenyi
Z
Liu
Jonghyeob
J
Lee
Meei-Hua
MH
Lin
Seth D
SD
Crosby
Christopher J
CJ
Roberts
Perry W
PW
Grigsby
Jeffrey H
JH
Miner
Andrew G
AG
Farr
Raphael
R
Kopan
D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency; D000818:Animals; D000831:Animals, Newborn; D001402:B-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D004817:Epidermis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D007958:Leukocyte Count; D008136:Longevity; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D011247:Pregnancy; D051880:Receptors, Notch / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D013997:Time Factors; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse