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

Abstract

AbstractNeutrophil 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. Down-regulation 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.