Estrogen receptor alpha modulates toll-like receptor signaling in murine lupus

• Published in: Clinical immunology (Orlando, Fla.) Vol. 144; no. 1; pp. 1 - 12
• Main Authors: Cunningham, Melissa A, Naga, Osama S, Eudaly, Jackie G, Scott, Jennifer L, Gilkeson, Gary S
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-07-2012; Elsevier
• Subjects: Allergy and Immunology; Animals; Autoantibodies; B-Lymphocytes - immunology; Biological and medical sciences; Bone Marrow Cells - cytology; CpG Islands - immunology; Cytokines - immunology; Dendritic cells; Dendritic Cells - immunology; Disease Models, Animal; Estradiol; Estrogen receptor alpha; Estrogen Receptor alpha - deficiency; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - immunology; Estrogen receptors; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genotypes; Guanosine - analogs & derivatives; Guanosine - pharmacology; Immunomodulation; Inflammation; Kidney diseases; Lupus Erythematosus, Systemic - immunology; Lupus nephritis; Lymphocytes B; Lymphocytes T; Medical sciences; Mice; Mice, Knockout; Proteinuria; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Spleen; Spleen - cytology; Systemic lupus erythematosus; Toll-like receptors; Toll-Like Receptors - agonists; Toll-Like Receptors - immunology; Toll-like receptors; Estrogen receptor alpha; Systemic lupus erythematosus; Dendritic cells; Immunopathology; Connective tissue disease; Dendritic cell; Estrogen receptor; Skin disease; Rodentia; Estrogen; Autoimmune disease; Toll like receptor; Ovarian hormone; Signal transduction; Vertebrata; Mammalia; Immunology; Mouse; Antigen presenting cell; Animal; Systemic disease; Sex steroid hormone; Hormonal receptor
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2012.04.001

Abstract Systemic lupus erythematosus (SLE) is a disease that disproportionately affects females. Despite significant research effort, the mechanisms underlying the female predominance in this disease are largely unknown. Previously, we showed that estrogen receptor alpha knockout (ERαKO) lupus prone female mice had significantly less pathologic renal disease and proteinuria, and significantly prolonged survival. Since autoantibody levels and number and percentage of B/T cells were not significantly impacted by ERα genotype, we hypothesized that the primary benefit of ERα deficiency in lupus nephritis was via modulation of the innate immune response. Using BMDCs and spleen cells/B cells from female wild-type or ERαKO mice, we found that ERαKO-derived cells have a significantly reduced inflammatory response after stimulation with TLR agonists. Our results indicate that the inflammatory response to TLR ligands is significantly impacted by the presence of ERα despite the absence of estradiol, and may partially explain the protective effect of ERα deficiency in lupus-prone animals.