Steroid hormone receptor expression and function in microglia

• Published in: Glia 2008-04, Vol.56 (6), p.659-674
• Main Authors: Sierra, Amanda, Gottfried-Blackmore, Andres, Milner, Teresa A., McEwen, Bruce S., Bulloch, Karen
• Format: Article
• Language: English
• Subjects: Animals; brain inflammation; Cells, Cultured; Cytokines - metabolism; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Down-Regulation - physiology; estradiol; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogens - pharmacology; Female; Flow Cytometry - methods; Gene Expression - drug effects; Gene Expression - physiology; glucocorticoids; Green Fluorescent Proteins - metabolism; LPS; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; microglia; Microglia - drug effects; Microglia - physiology; Microglia - ultrastructure; Microscopy, Immunoelectron - methods; Ovariectomy; receptors; Receptors, Steroid - physiology; Sex Characteristics; steroid hormones; Time Factors
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.20644

Steroid hormones such as glucocorticoids and estrogens are well‐known regulators of peripheral immune responses and also show anti‐inflammatory properties in the brain. However, the expression of steroid hormone receptors in microglia, the pivotal immune cell that coordinates the brain inflammatory response, is still controversial. Here we use real time RT‐PCR to show that microglia, isolated from adult fms‐EGFP mice by FACS, express glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and estrogen receptor alpha (ERα). GR was the most abundant steroid hormone receptor transcript in microglia. The presence of GR and ERα immunoreactivity was further confirmed in vivo at the ultrastructural level. To understand the role of steroid hormone receptors during the inflammation process, we evaluated the expression of steroid hormone receptors after inflammatory challenge and found a significant down‐regulation of GR, MR, and ERα in microglia. Finally, we tested the immunomodulatory properties of estrogens and glucocorticoids. Estradiol benzoate did not have any significant impact on the inflammatory profile of ex vivo sorted microglia, either in resting conditions or after challenge. Furthermore, corticosterone was a more consistent anti‐inflammatory agent than 17β‐estradiol in vitro. Our results support the hypothesis that adult microglia are a direct target of steroid hormones and that glucocorticoids, through the predominant expression of GR and MR, are the primary steroid hormone regulators of microglial inflammatory activity. The down‐regulation of steroid hormone receptors after LPS challenge may serve as a prerequisite to suppressing the anti‐inflammatory actions of endogenous steroid hormones on the immune system, and contribute to a sustained activation of microglia. © 2008 Wiley‐Liss, Inc.