Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells.
Langerhans cell histiocytosis (LCH) is an enigmatic disease defined by the accumulation of Langerhans cell-like dendritic cells (DCs). In the present study, we demonstrate that LCH cells exhibit a unique transcription profile that separates them not only from plasmacytoid and myeloid DCs, but also from epidermal Langerhans cells, indicating a distinct DC entity. Molecular analysis revealed that isolated and tissue-bound LCH cells selectively express the Notch ligand Jagged 2 (JAG2) and are the only DCs that express both Notch ligand and its receptor. We further show that JAG2 signaling induces key LCH-cell markers in monocyte-derived DCs, suggesting a functional role of Notch signaling in LCH ontogenesis. JAG2 also induced matrix-metalloproteinases 1 and 12, which are highly expressed in LCH and may account for tissue destruction in LCH lesions. This induction was selective for DCs and was not recapitulated in monocytes. The results of the present study suggest that JAG2-mediated Notch activation confers phenotypic and functional aspects of LCH to DCs; therefore, interference with Notch signaling may be an attractive strategy to combat this disease.
St Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria. caroline.hutter@stanna.at
Caroline
C
Hutter
Max
M
Kauer
Ingrid
I
Simonitsch-Klupp
Gunhild
G
Jug
Raphaela
R
Schwentner
Judith
J
Leitner
Peter
P
Bock
Peter
P
Steinberger
Wolfgang
W
Bauer
Nadia
N
Carlesso
Milen
M
Minkov
Helmut
H
Gadner
Georg
G
Stingl
Heinrich
H
Kovar
Ernst
E
Kriehuber
D000293:Adolescent; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006646:Histiocytosis, Langerhans-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072101:Jagged-2 Protein; D007801:Langerhans Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059467:Transcriptome
D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1