17β‐Oestradiol Anti‐Inflammatory Effects in Primary Astrocytes Require Oestrogen Receptor β‐Mediated Neuroglobin Up‐Regulation

Abstract

Neuroglobin (Ngb), so named after its initial discovery in brain neurones, has received great attention as a result of its neuroprotective effects both in vitro and in vivo. Recently, we demonstrated that, in neurones, Ngb is a 17β-oestradiol (E(2) ) inducible protein that is pivotal for hormone-induced anti-apoptotic effects against H(2) O(2) toxicity. The involvement of Ngb in other brain cell populations, as well as in other neuroprotective effects of E(2) , is completely unknown at present. We demonstrate Ngb immunoreactivity in reactive astrocytes located in the proximity of a penetrating cortical injury in vivo and the involvement of Ngb in the E(2) -mediated anti-inflammatory effect in primary cortical astrocytes. Upon binding to oestrogen receptor (ER)β, E(2) enhances Ngb levels in a dose-dependent manner. Although with a lesser degree than E(2) , the pro-inflammatory stimulation with lipopolysaccharide (LPS) also induces the increase of Ngb protein levels via nuclear factor-(NF)κB signal(s). Moreover, a negative cross-talk between ER subtypes and NFκB signal(s) has been demonstrated. In particular, ERα-activated signals prevent the NFκB-mediated Ngb increase, whereas LPS impairs the ERβ-induced up-regulation of Ngb. Therefore, the co-expression of both ERα and ERβ is pivotal for mediating E(2) -induced Ngb expression in the presence of NFκB-activated signals. Interestingly, Ngb silencing prevents the effect of E(2) on the expression of inflammatory markers (i.e. interleukin 6 and interferon γ-inducible protein 10). Ngb can be regarded as a key mediator of the different protective effects of E(2) in the brain, including protection against oxidative stress and the control of inflammation, both of which are at the root of several neurodegenerative diseases.

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

“…For each steroid receptor, strongly coexpressed genes within a brain region are likely related to the localized functional role of the receptor. For example, of the top 10 genes coexpressed with Esr1 across the whole brain, four were previously shown to be regulated by ESR1 and/or estrogens in various tissues (Gpr101, Calcr, Ngb, and Gpx3) (12)(13)(14)(15). These genes were also coexpressed with Esr1 in the HY, in line with their functional relationship to Esr1 in mediating, for example, reproductive and metabolic processes.…”

Involvement of decreased neuroglobin protein level in cognitive dysfunction induced by 1-bromopropane in rats

“…The current study demonstrated that 1-BP treatment decreased Ngb protein level in cerebral cortex in a dose-dependent manner. Ngb was expressed in neurons as well as astrocytes (De Marinis et al, 2013a, 2013b. Therefore, Ngb decrease induced by 1-BP made the cortical neurons more vulnerable to damage by reactive species and apoptosis which could cause neuron loss.…”

“…Ngb, firstly discovered in 2000, is expressed in neurons, astrocytes, retina and some endocrine tissues (Burmester et al, 2000;Burmester and Hankeln, 2004;De Marinis et al, 2013a). Brunori and Vallone (2007) demonstrated its highly conserved structure and function.…”

Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats

“…It has been reported that the two classic receptors for estrogen, estrogen receptor α (ERα), and estrogen receptor β (ERβ) are closely related with inflammation [11][12][13]. In contrast to the long association of ERα with pain, the association of ERβ with pain may have a totally contradictory role to that mediated by ERα [14][15][16].…”