Estrogen receptor alpha modulates Toll-like receptor signaling in murine lupus.
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.
Medical University of South Carolina, Division of Rheumatology and Immunology and Ralph H. Johnson Veterans Affairs Hospital, Charleston, SC 29425, USA.
Melissa A
MA
Cunningham
Osama S
OS
Naga
Jackie G
JG
Eudaly
Jennifer L
JL
Scott
Gary S
GS
Gilkeson
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology*
D016207:Cytokines; D047628:Estrogen Receptor alpha; D051193:Toll-Like Receptors; D006151:Guanosine; C068562:loxoribine