Estrogen receptors regulate an inflammatory pathway of dendritic cell differentiation: Mechanisms and implications for immunity

This article is part of a Special Issue Neuroendocrine-Immune Axis in Health and Disease. Immune cells and hematopoietic progenitors express estrogen receptors (ER). As ligand-activated transcription factors that modulate chromatin structure, ER regulate transcriptional programs that direct the development or functional responses of immune cells. ER-regulated immune responses likely contribute to significant sex biases in infection, autoimmunity and other inflammatory diseases, and changes in immune function during the female hormonal cycle and pregnancy. Here we summarize our own and others' studies showing that ER alpha signaling regulates the development of dendritic cells (DCs), antigen-presenting cells crucial for initiation of innate and adaptive immunity. During inflammation, elevated GM-CSF directs the development of new DCs from monocytes or other precursors that infiltrate tissues and lymphoid organs, and these de novo populations of inflammatory DCs have critical roles in programming T cell-mediated responses during infection and autoimmunity. Estradiol acting via ER alpha, but not ER beta, promotes the GM-CSF-mediated inflammatory pathway of DC differentiation, leading to the development of DCs with increased functional capacity. Estradiol/ER alpha signaling acts directly in GM-CSF-stimulated myeloid progenitors to induce elevated levels of IRF4, a transcription factor that directs a developmental program underlying CD11b(+) DC differentiation. In contrast, during homeostatic Flt3 Ligand-driven DC development, ER alpha signaling decreases numbers of myeloid progenitors and differentiated DCs, yet promotes more functionally competent DCs. Thus ER alpha signaling regulates the response of DC progenitors to the external cytokine environment, thereby altering the strength or integrity of DC developmental pathways. The development of increased numbers of DCs during inflammation will likely increase the magnitude of DC-mediated functional responses including cytokine production, processing and MHC-mediated presentation of antigens, and activation and polarization of T and B lymphocytes; these functions also may be regulated directly by ER alpha signaling. In sum, via profound effects on DC development and ensuing functional responses, ER alpha signaling can regulate the quality of the adaptive immune responses and influence the resolution of infection or chronic inflammatory diseases. (C) 2012 Elsevier Inc. All rights reserved.