Shaping Microglial Phenotypes Through Estrogen Receptors: Relevance to Sex-Specific Neuroinflammatory Responses to Brain Injury and Disease.

In mammals, 17β-estradiol (E2), the primary endogenous estrogen, maintains normal central nervous system (CNS) function throughout life and influences brain responses to injury and disease. Estradiol-induced cellular changes are mediated through the activation of nuclear and extranuclear estrogen receptors (ERs), which include ERα, ERβ, and the G-protein coupled receptor, GPER1. ERs are widely expressed throughout the brain, acting as transcriptional effectors or rapidly initiating membrane and cytoplasmic signaling cascades in practically all brain cells including microglia, the resident immune cells of the CNS. Activation of ERs by E2 exerts potent anti-inflammatory effects through mechanisms involving the modification of microglial cell responses to acute or chronic brain injury. Recent studies suggest that microglial maturation is influenced by the internal gonadal hormone milieu and that their functions in the normal and diseased brain are sex specific. However, the role that each ER subtype plays in microglial development or in determining microglial function as the primary cellular defense mechanism against pathogens and injury remains unclear. This is partly due to the fact that most studies investigating the mechanisms by which E2-ER signaling modifies microglial cellular phenotypes have been restricted to one sex or age. This review examines the different in vivo and in vitro models used to study the direct and indirect regulation of microglial cell function by E2 through ERs. Ischemic stroke will be used as an example of a neurologic disease in which activation of ERs shapes microglial phenotypes in response to injury in a sex- and age-specific fashion. SIGNIFICANCE STATEMENT: As the primary immune sensors of central nervous system damage, microglia are important potential therapeutic targets. Estrogen receptor signaling modulates microglial responses to brain injury and disease in a sex- and age-specific fashion. Hence, investigating the molecular mechanisms by which estrogen receptors regulate and shape microglial functions throughout life may result in novel and effective therapeutic opportunities that are tailored for each sex and age.