title: Estrogen Receptor α Deficiency Modulates TLR Ligand-Mediated PDC-TREM Expression in Plasmacytoid Dendritic Cells in Lupus-Prone Mice.
abstract: Female lupus-prone NZM2410 estrogen receptor α (ERα)-deficient mice are protected from renal disease and have prolonged survival compared with wild-type littermates; however, the mechanism of protection is unknown. Plasmacytoid dendritic cells (pDCs) and type I IFN drive lupus pathogenesis. Estrogen acting via ERα enhances both pDC development and IFN production. The objectives for this study were to determine if ERα modulates pDC function and IFN activity in predisease NZM2410 mice as a possible protective mechanism of ERα deficiency in lupus-prone mice. We measured the effect of ERα deficiency on spleen pDC frequency, number, maturation, and activation state. ERα deficiency reduced type I IFN activity and the frequency of MHC class II(+) pDCs in the spleen without altering overall pDC frequency, number, or maturation state. Additionally, ERα-deficient NZM2410 mice had a significantly decreased frequency of pDCs expressing PDC-TREM, a modulator of TLR-mediated IFN production. After in vitro TLR9 stimulation, ERα deficiency significantly reduced the expression of PDC-TREM on pDCs from both NZM2410 and C57BL/6 mice. Thus, we have identified a significant effect of ERα deficiency on pDCs in predisease NZM2410 mice, which may represent a mechanism by which ERα deficiency protects NZM2410 mice from lupuslike disease.
authors.affiliation: Department of Microbiology and Immunology, College of Graduate Studies, Medical University of South Carolina, Charleston, SC 29425; Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Scott
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Melissa A
authors.identifier: http://orcid.org/0000-0002-9207-1986
authors.initials: MA
authors.lastname: Cunningham
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Osama S
authors.identifier: http://orcid.org/0000-0002-3655-7850
authors.initials: OS
authors.lastname: Naga
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Jena R
authors.identifier: http://orcid.org/0000-0001-6094-8336
authors.initials: JR
authors.lastname: Wirth
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Jackie G
authors.initials: JG
authors.lastname: Eudaly
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403 gilkeson@musc.edu.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D047628:Estrogen Receptor alpha / Q000172:deficiency*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056747:Immunomodulation; D007370:Interferon Type I / Q000378:metabolism; D007668:Kidney / Q000503:physiopathology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D007370:Interferon Type I; C528406:PDC-TREM protein, mouse; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9