Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation

Abstract

In CNS, glucocorticoids (GCs) activate both GC receptor (GR) and mineralocorticoid receptor (MR), whereas GR is widely expressed, the expression of MR is restricted. However, both are present in the microglia, the resident macrophages of the brain and their activation can lead to pro-or anti-inflammatory effects. We have therefore addressed the specific functions of GR in microglia. In mice lacking GR in macrophages/microglia and in the absence of modifications in MR expression, intraparenchymal injection of lipopolysaccharide (LPS) activating Toll-like receptor 4 signaling pathway resulted in exacerbated cellular lesion, neuronal and axonal damage. Global inhibition of GR by RU486 pre-treatment revealed that microglial GR is the principal mediator preventing neuronal degeneration triggered by lipopolysaccharide (LPS) and contributes with GRs of other cell types to the protection of non-neuronal cells. In vivo and in vitro data show GR functions in microglial differentiation, proliferation and motility. Interestingly, microglial GR also abolishes the LPS-induced delayed outward rectifier currents by downregulating Kv1.3 expression known to control microglia proliferation and oxygen radical production. Analysis of GR transcriptional function revealed its powerful negative control of pro-inflammatory effectors as well as upstream inflammatory activators. Finally, we analyzed the role of GR in chronic unpredictable mild stress and aging, both known to prime or sensitize microglia in vivo. We found that microglial GR suppresses rather than mediates the deleterious effects of stress or aging on neuronal survival. Overall, the results show that microglial GR acts on several key processes limiting pro-inflammatory actions of activated microglia.

Live imaging of the innate immune response in neonates reveals differential TLR2 dependent activation patterns in sterile inflammation and infection

“…Although previous evidence demonstrated that in the adult brain, the systemic LPS-induced innate immune response is mediated by the resident microglia and does not lead to infiltration of the peripheral cells (Chen et al, 2012), the cellular response to LPS in immature brain is less well characterized (Cazareth et al, 2014; Pierre et al, 2016). Namely, report by Carrillo-de Savage and colleagues suggests that (Carrillo-de Sauvage et al, 2013) intraparenchymal injection of LPS may induce cell proliferation and/or infiltration of myeloid cells from the periphery. To decipher cellular components of LPS –mediated innate immune response and TLR2-luc signal induction in immature brain, we performed flow cytometry.…”

Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity

“…Regardless, of the type of retinal damage, GCR agonist suppressed microglial reactivity and protected retinal neurons against damage. Similarly, the anti-inflammatory effects of glucocorticoids on microglia in the brain are believed to be neuroprotective (Carrillo-de Sauvage et al 2013; Golde et al 2003; Nadeau and Rivest 2003). In the CNS, the neuroendocrine system exerts influence on immune responses through activation of steroid hormone receptors (Sternberg 2006).…”

“…Treatment with Dex can decrease iNOS-mediated toxicity of microglia (Golde et al 2003), and inhibition of the GCR-signaling can exacerbate cell damage resulting from the pro-inflammatory actions of lipopolysaccharide (Nadeau and Rivest 2003). Further, a recent study has shown that GCR acts on several key processes limiting proinflammatory actions of activated microglia (Carrillo-de Sauvage et al 2013). Given that activated nuclear GCR in the retina is predominantly found in Müller glia, not microglia (Gallina et al 2014), we propose that the anti-inflammatory effects of Dex on microglia are indirectly elicited through the Müller glia.…”

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

“…However, a role for inflammation in regulating regeneration following selective neuronal cell ablation has yet to be investigated. Activation of glucocorticoid signaling has been shown to reduce microglial reactivity in the mammalian brain (47,48) and chick retina (49). Therefore, using the intravital imaging techniques detailed above, we first investigated whether exposing larvae to Dex before Mtz-induced rod cell ablation would result in a reduction in microglia migration.…”