Down-regulation of RXRalpha expression is essential for neutrophil development from granulocyte/monocyte progenitors.
Neutrophil granulocytes (Gs) represent highly abundant and short-lived leukocytes that are constantly regenerated from a small pool of myeloid committed progenitors. Nuclear receptor (NR) family members are ligand-activated transcription factors that play key roles in cellular proliferation and differentiation processes including myelopoiesis. Retinoid X receptor alpha (RXRalpha) represents the predominant NR types I and II homo- and heterodimerization partner in myeloid cells. Here we show that human myeloid progenitors express RXRalpha protein at sustained high levels during macrophage colony-stimulating factor (M-CSF)-induced monopoiesis. In sharp contrast, RXRalpha is down-regulated during G-CSF-dependent late-stage neutrophil differentiation from myeloid progenitors. Down-regulation of RXRalpha is critically required for neutrophil development since ectopic RXRalpha inhibited granulopoiesis by impairing proliferation and differentiation. Moreover, ectopic RXRalpha was sufficient to redirect G-CSF-dependent granulocyte differentiation to the monocyte lineage and to promote M-CSF-induced monopoiesis. Functional genetic interference with RXRalpha signaling in hematopoietic progenitor/stem cells using a dominant-negative RXRalpha promoted the generation of late-stage granulocytes in human cultures in vitro and in reconstituted mice in vivo. Therefore, our data suggest that RXRalpha down-regulation is a critical requirement for the generation of neutrophil granulocytes.
Taschner
Sabine
S
Institute of Immunology, Medical University Vienna, Austria.
Koesters
Christina
C
Platzer
Barbara
B
Jörgl
Almut
A
Ellmeier
Wilfried
W
Benesch
Thomas
T
Strobl
Herbert
H
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology*; D038042:Myelopoiesis / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology*; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D014161:Transduction, Genetic
D047490:Retinoid X Receptor alpha; D016173:Macrophage Colony-Stimulating Factor