Regulation of brain microglia by female gonadal steroids

• We describe the susceptibility of murine microglia to hypoxia.
• Estrogen and progesterone inhibit hypoxia-induced expression of pro-inflammatory cytokines.
• Sex steroids induce the switch of a pro-inflammatory M1 to a more protective M2 microglia phenotype.

Microglial cells are the primary mediators of the CNS immune defense system and crucial for shaping inflammatory responses. They represent a highly dynamic cell population which is constantly moving and surveying their environment. Acute brain damage causes a local attraction and activation of this immune cell type which involves neuron-to-glia and glia-to-glia interactions. The prevailing view attributes microglia a “negative” role such as defense and debris elimination. More topical studies also suggest a protective and “positive” regulatory function. Estrogens and progestins exert anti-inflammatory and neuroprotective effects in the CNS in acute and chronic brain diseases. Recent work revealed that microglial cells express subsets of classical and non-classical estrogen and progesterone receptors in a highly dynamic way. In this review article, we would like to stress the importance of microglia for the spreading of neural damage during hypoxia, their susceptibility to functional modulation by sex steroids, the potency of sex hormones to switch microglia from a pro-inflammatory M1 to neuroprotective M2 phenotype, and the regulation of pro- and anti-inflammatory properties including the inflammasome. We will further discuss the possibility that the neuroprotective action of sex steroids in the brain involves an early and direct modulation of local microglia cell function.This article is part of a Special Issue entitled ‘Sex steroids and brain disorders’.