Down-regulation of RXRα expression is essential for neutrophil development from granulocyte/monocyte progenitors

Abstract

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 (RXRα) represents the predominant NR types I and II homo- and heterodimerization partner in myeloid cells. Here we show that human myeloid progenitors express RXRα protein at sustained high levels during macrophage colony-stimulating factor (M-CSF)-induced monopoiesis. In sharp contrast, RXRα is down-regulated during G-CSF-dependent late-stage neutrophil differentiation from myeloid progenitors. Downregulation of RXRα is critically required for neutrophil development since ectopic RXRα inhibited granulopoiesis by impairing proliferation and differentiation. Moreover, ectopic RXRα was sufficient to redirect G-CSF-dependent granulocyte differentiation to the monocyte lineage and to promote M-CSF-induced monopoiesis. Functional genetic interference with RXRα signaling in hematopoietic progenitor/stem cells using a dominant-negative RXRα promoted the generation of late-stage granulocytes in human cultures in vitro and in reconstituted mice in vivo. Therefore, our data suggest that RXRα down-regulation is a critical requirement for the generation of neutrophil granulocytes. © 2007 by The American Society of Hematology.