Estrogen receptor signaling promotes dendritic cell differentiation by increasing expression of the transcription factor IRF4

During inflammation, elevated granulocyte macrophage–colony-stimulating factor (GM-CSF) directs the development of new dendritic cells (DCs). This pathway is influenced by environmental factors, and we previously showed that physiologic levels of estradiol, acting through estrogen receptor alpha (ERα), promote the GM-CSF–mediated differentiation of a CD11b+ DC subset from myeloid progenitors (MPs). We now have identified interferon regulatory factor 4 (IRF4), a transcription factor induced by GM-CSF and critical for CD11b+ DC development in vivo, as a target of ERα signaling during this process. In MPs, ERα potentiates and sustains GM-CSF induction of IRF4. Furthermore, retroviral delivery of the Irf4 cDNA to undifferentiated ERα−/− bone marrow cells restored the development of the estradiol/ERα-dependent DC population, indicating that an elevated amount of IRF4 protein substitutes for ERα signaling. Thus at an early stage in the MP response to GM-CSF, ERα signaling induces an elevated amount of IRF4, which leads to a developmental program underlying CD11b+ DC differentiation.