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 (ER alpha KO) lupus prone female mice had significantly less pathologic renal disease and proteinuria, and significantly prolonged survival. Since autoantibody levels and number and percentage of BIT cells were not significantly impacted by ER alpha genotype, we hypothesized that the primary benefit of ERa deficiency in lupus nephritis was via modulation of the innate immune response. Using BMDCs and spleen cells/B cells from female wild-type or ER alpha KO mice, we found that ER alpha KO-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 ER alpha despite the absence of estradiot, and may partially explain the protective effect of ER alpha deficiency in lupus-prone animals. (C) 2012 Published by Elsevier Inc.