Background Estrogen is anti- or pro-inflammatory depending on milieu and plays a role in the increased incidence of lupus in reproductive age women. Estrogen’s pleiotropic effects are in part due to estrogen receptors (ER) and their variants that localize to different regions in the cell. To understand the role of ERα localization in immune responses, we investigated the effects of altered ERα localization on Toll Like Receptor (TLR7)-stimulated endpoints, often dysregulated in lupus.
Methods Membrane-only ERα (MOER) or Nuclear-only ERα (NOER) mice were used to isolate and culture spleen cells, ex vivo bone marrow (BM), and BM-DCs. Cells were phenotyped via flow cytometry to identify immune cell subsets. Spleen cells were treated with vehicle or TLR7/8 agonist overnight prior to supernatant analysis. In a parallel experiment, mice were treated for two weeks with a topical TLR7 agonist (R848) to assess effects on immune cell populations.
Results Immune cell subsets in spleen were similar in all mice. Cell counts of ex vivo and Flt3L- cultured BM-DCs were reduced in NOER mice. Conventional DCs (cDCs) were increased in MOER mice, and NOER mice trended higher in CD19+ cells. Other immune populations remained similar. NOER mice trended lower in IL-6 response after overnight R848 stimulation.
Conclusion Preliminary results suggest membrane ERα-initiated events are required to develop certain innate immune cell subsets and for robust expansion of DCs. Membrane and nuclear functions of ERα may compensate for each other in some cases. More studies are needed to clarify the role of ERα localization in modulating immune cell development and function.
Sources of Support K08 AR068471 NIH/NIAMS (Cunningham); American College of Rheumatology (ACR) RRF K to R Bridge
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