Estrogen receptor alpha is required for macrophage iron sequestration and homeostasis in female mice (INM1P.438)

Abstract

Abstract Sexual dimorphisms in immunity are known to confer protection against infections at the cost of heightened risk for autoimmunity in women. The female sex hormone, estradiol, can modulate both pro/anti-inflammatory macrophage signals and the mechanisms of action remain unclear. Iron sequestration by macrophages is fundamentally important to limit bacterial infection, and since estradiol is thought to influence iron metabolism in females, we asked whether ERα impacts the innate immune response by regulating macrophage iron metabolism. To address this question, we crossed floxed Esr1 (fl/fl control) and LysM-Cre transgenic animals to generate myeloid-specific ERα knockout (MACER) mice. We studied the effect of ERα deletion on iron homeostasis upon endotoxin treatment in female MACER and fl/fl conrols. MACER mice had increased serum iron (92%; p=0.01) compared to fl/fl under basal conditions. As expected, endotoxin treatment reduced serum iron levels in fl/fl controls (41%, p=.008), however there was no change in serum iron in MACER mice. Consistent with impaired macrophage iron homeostasis, expression of genes associated with iron absorption (TfR, Slc11a2, Cybrd1), efflux (Fpn), and storage (Ftl) were significantly altered in female MACER mice compared to fl/fl controls. Together, these data suggest that ERα regulates macrophage iron metabolism in females, is required for systemic iron homeostasis, and may play a previously unrecognized role in female innate immunity.