Microglia express functional 11β‐hydroxysteroid dehydrogenase type 1

Abstract

Glucocorticoids are potent regulators of inflammation exerting permissive, stimulatory, and suppressive effects. Glucocorticoid access to intracellular receptors is regulated by the activity of two distinct enzymes known as 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) Type 1 and Type 2, which catalyze the activation or deactivation of glucocorticoids. Although expression of these enzymes in major organ systems and their roles in the metabolic effects of glucocorticoids have been described, their role in the inflammatory response has only recently started to be addressed. In this report, we have studied the expression and activity of 11 beta HSD Type 1 and Type 2 in microglia cells. Microglia, the brain's resident macrophages, initiate and orchestrate CNS inflammatory responses. Importantly, activated microglia are implicated in most neurodegenerative conditions, making them key subjects of study. We found that microglia expressed 11 beta HSD-1, but not 11 beta HSD-2, both in ex vivo FACS-sorted adult cells and in vitro primary cultures. 11 beta HSD-1 expression was increased in LPS-activated microglia. Moreover, 11 beta HSD-1 catalyzed the metabolic conversion of 11-dehydro-corticosterone into corticosterone (CORT), which potently reduced cytokine production in activated microglia. We propose that 11 beta HSD-1 may provide microglia with an intrinsic mechanism to autoregulate and inhibit proinflammatory mediator production through CORT formation.

Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation

“…Pla2g5, which codes for a secreted phospholipase A 2 that regulates the synthesis of inflammatory mediators (arachidonic acid, prostaglandins, leukotrienes, and platelet-activating factor) (Murakami et al 1997), the mobilization of macrophages (Ruiperez et al 2009)and leucocytes (Lapointe et al 2010), and microglial inflammatory responses (Yang et al 2009) was also increased in expression with aging. Genes involved in the production of neurosteroids which control the magnitude and duration of microglial activation (Sierra et al 2008; Gottfried-Blackmore et al 2010; Saijo et al 2011) were also altered in expression. A down-regulated gene, Hsd17b1 , codes for 11β-hydroxysteroid dehydrogenase type 1, which activates the glucocorticoid cortisone (Seckl & Walker 2001) and induces the production of steroid hormone 5-androsten-3β,17β-diol (ADIOL) (Moeller & Adamski 2009), a key factor in limiting microglial activation (Gottfried-Blackmore et al 2010; Saijo et al 2011).…”

“…Genes involved in the production of neurosteroids which control the magnitude and duration of microglial activation (Sierra et al 2008; Gottfried-Blackmore et al 2010; Saijo et al 2011) were also altered in expression. A down-regulated gene, Hsd17b1 , codes for 11β-hydroxysteroid dehydrogenase type 1, which activates the glucocorticoid cortisone (Seckl & Walker 2001) and induces the production of steroid hormone 5-androsten-3β,17β-diol (ADIOL) (Moeller & Adamski 2009), a key factor in limiting microglial activation (Gottfried-Blackmore et al 2010; Saijo et al 2011). As a result, age-related changes in these lipid biosynthetic pathways may underlie altered activation responses in aged microglia.…”

Glucocorticoid-Dependent Hippocampal Transcriptome in Male Rats: Pathway-Specific Alterations With Aging

“…Strengthening of the direct-mode results from increased binding of GR dimers to both pGREs and nGREs. Several aging-related changes that could lead to such increased ligand-activated GR binding to GREs have been described, including an increase in circulating GCs, found in many, but not all, rodent and human studies (16, 56, 79, 82, 118), a rise in the 11β-hydroxysteroid dehydrogenase type I to type II ratio (54, 119, 120), or increased expression of GRs and/or epigenetic cofactors (53, 54, 74, 81, 121, 122). (The genes encoding the MR [ Nr3C2 ] and the GR [ Nr3C1 ] were repressed by CORT, but only Nr3C2 was changed [down-regulated] with age as shown in Supplemental Table 1.…”

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…Whereas incubation of human monocytes with bacterial lipopolysaccharide (LPS) has no effect on 11␤-HSD1, in macrophages 11␤-HSD1 is increased following LPS activation (termed "classical activation") (326, 433, 703) (FIGURE 10), which polarizes macrophages to a pro-inflammatory M1 phenotype. Similarly, LPS induces 11␤-HSD1 mRNA in microglia, the brain's resident macrophages, although curiously this is not accompanied by changes in protein (243).…”