Estradiol Acts Directly on Bone Marrow Myeloid Progenitors to Differentially Regulate GM-CSF or Flt3 Ligand-Mediated Dendritic Cell Differentiation

Abstract

Estrogen receptor (ER) ligands modulate hemopoiesis and immunity in the normal state, during autoimmunity, and after infection or trauma. Dendritic cells (DC) are critical for initiation of innate and adaptive immune responses. We demonstrate, using cytokine-driven culture models of DC differentiation, that 17-β-estradiol exerts opposing effects on differentiation mediated by GM-CSF and Flt3 ligand, the two cytokines that regulate DC differentiation in vivo. We also show that estradiol acts on the same highly purified Flt3+ myeloid progenitors (MP) to differentially regulate the DC differentiation in each model. In GM-CSF-supplemented cultures initiated from MP, physiological amounts of estradiol promoted differentiation of Langerhans-like DC. Conversely, in Flt3 ligand-supplemented cultures initiated from the same MP, estradiol inhibited cell survival in a dose-dependent manner, thereby decreasing the yield of plasmacytoid and conventional myeloid and lymphoid DC. Experiments with bone marrow cells from ER-deficient mice and the ER antagonist ICI182,780 showed that estradiol acted primarily via ERα to regulate DC differentiation. Thus, depending on the cytokine environment, pathways of ER signaling and cytokine receptor signaling can differentially interact in the same Flt3+ MP to regulate DC development. Because the Flt3 ligand-mediated differentiation pathway is important during homeostasis, and GM-CSF-mediated pathways are increased by inflammation, our data suggest that endogenous or pharmacological ER ligands may differentially affect DC development during homeostasis and disease, with consequent effects on DC-mediated immunity.

Estrogens and atherosclerosis: insights from animal models and cell systems

“…The same group noticed that ERa-mediated signaling is required for optimal dendritic cell function as assessed by MHC-II and CD86 expression and pro-inflammatory cytokine production (IL6 and IL12) and that estrogens enhance susceptibility to experimental myasthenia gravis by augmenting dendritic cell activation and proinflammatory Th1 response (Delpy et al 2005, Douin-Echinard et al 2008. The pivotal role of estrogens in regulating dendritic cell differentiation and activation was also highlighted in other studies, in which E 2 was shown to support GM-CSF-initiated transition of bone marrow progenitor cells into dendritic cells, to prevent apoptosis, and to augment the production of proinflammatory and pro-atherogenic cytokines IL12 and IFNg by dendritic cells in response to TLR4 or TLR7 agonists (Carreras et al 2008, Kawasaki et al 2008, Siracusa et al 2008). The reasons why estrogens differentially affect macrophage and dendritic cell activation in vitro and in vivo and thereby exert dual effects on inflammation are currently unclear (see Straub (2007) for exhaustive discussion).…”

Estradiol Promotes Functional Responses in Inflammatory and Steady-State Dendritic Cells through Differential Requirement for Activation Function-1 of Estrogen Receptor α

“…This regulatory action of estrogens on immune responses and autoimmunity are thought to be due to a direct action on immunocompetent cells of the innate and adaptive immune systems (4), which have been recently shown to functionally express ERs, particularly ERa (5)(6)(7)(8)(9)(10)(11). Alternatively, estrogens, through their ERs, may act on precursor cells to regulate the differentiation and functions of lymphoid and myeloid cells (12)(13)(14)(15)(16)(17)(18).…”

“…Several studies have shown a role for ERa signaling in the differentiation and functions of various DC subsets not only in vitro (13,(16)(17)(18), but also in vivo (11). DCs can be generated from bone marrow (BM) precursors cultured in the presence of GM-CSF or Flt3 ligand (Flt3L).…”

The identification and enumeration of dendritic cell populations from individual mouse spleen and Peyer's patches using flow cytometric analysis

“…However, the authors' used the DC properties of low buoyant density and adherence to glass to isolate and enrich for DCs (14). A variety of factors may influence the number of DCs in a tissue or animal at a given time, including infection, chronic disease states such as diabetes, hormones such as estradiol, nutrients such as vitamins A and D, as well as others (15)(16)(17)(18)(19)(20). However, previous methods used to analyze DCs have used enrichment techniques from pooled samples, either multiple tissue or animal sources, to obtain sufficient numbers of cells for analysis leading to potentially high variability and inaccurate DC number assessments.…”