Down-regulation of RXRα 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. Retinold X receptor alpha (RXR alpha) represents the predominant NR types I and 11 homo- and heterodimerization partner in myelold cells. Here we show that human myeloid progenitors express RxR alpha protein at sustained high levels during macrophage colony-stimulating factor (M-CSF)-induced monopolesis. In sharp contrast, RXR alpha, is down-regulated during G-CSFdependent late-stage neutrophil differentiation from myelold progenitors. Downregulation of RXR alpha is critically required for neutrophil development since ectopic RXR alpha, inhibited granulopolesis by impairing proliferation and differentiation. Moreover, ectopic RXR alpha was sufficient to redirect G-CSF-dependent granulocyte differentiation to the monocyte lineage and to promote M-CSF-induced monopolesis. Functional genetic interference with RXR alpha, signaling in hematopoletic progenitor/stem cells using a dominant-negative RXR alpha promoted the generation of latestage granulocytes in human cultures in vitro and in reconstituted mice in vivo. Therefore, our data suggest that RXR alpha down-regulation is a critical requirement for the generation of neutrophil granulocytes.