Brain microglia express steroid-converting enzymes in the mouse

Abstract

In the CNS, steroid hormones play a major role in the maintenance of brain homeostasis and it's response to injury. Since activated microglia are the pivotal immune cell involved in neurodegeneration, we investigated the possibility that microglia provide a discrete source for the metabolism of active steroid hormones. Using RT-PCR, our results showed that mouse microglia expressed mRNA for 17beta-hydroxysteroid dehydrogenase type 1 and steroid 5alpha-reductase type 1, which are involved in the metabolism of androgens and estrogens. Microglia also expressed the peripheral benzodiazepine receptor and steroid acute regulatory protein; however, the enzymes required for de novo formation of progesterone and DHEA from cholesterol were not expressed. To test the function of these enzymes, primary microglia cultures were incubated with steroid precursors, DHEA and AD. Microglia preferentially produced delta-5 androgens (Adiol) from DHEA and 5alpha-reduced androgens from AD. Adiol behaved as an effective estrogen receptor agonist in neuronal cells. Activation of microglia with pro-inflammatory factors, LPS and INFgamma did not affect the enzymatic properties of these proteins. However, PBR ligands reduced TNFalpha production signifying an immunomodulatory role for PBR. Collectively, our results suggest that microglia utilize steroid-converting enzymes and related proteins to influence inflammation and neurodegeneration within microenvironments of the brain.

Small molecule glutaminase inhibitors block glutamate release from stimulated microglia

“…Single suspension cells were prepared from whole brains of 1 - 2 d old mice, as described previously [18]. Cells were cultured in flasks in high glucose DMEM with 15% FBS.…”

Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity

“…Others [81] used the transgene to monitor recruitment and morphological changes in a kainic acid neurotoxicity model. And finally, Gottfried-Blackmore [82] isolated microglia from normal brain and showed that they express mRNA for steroidogenic enzymes, 17bHSD1 and Steroid 5-␣-reductase type 1, also used to demonstrate a microglial response to systemic LPS.…”

Dehydroepiandrosterone and age-related cognitive decline

“…The proteins and enzymes necessary for the conversion of DHEA/S to estradiol, as well as for the synthesis of DHEA/S from cholesterol (Fig. 1), are present in a region-dependent manner in the rodent brain (Zwain and Yen 1999; Hojo et al 2003; Kohchi et al 1998; Gottfried-Blackmore et al 2008), suggesting that this may be a valid mechanism of action. Interestingly, adrenalectomy combined with gonadectomy has no effect on the central levels of DHEA/S in rodents (Robel et al 1987) and suppression of adrenal activity with dexamethasone has no effect on DHEA/S levels in the nonhuman primate brain (Corpechot et al 1981), suggesting that the hormone is indeed synthesized de novo from cholesterol in the brain.…”