G-Protein-Coupled Estrogen Receptor Activation Upregulates Interleukin-1 Receptor Antagonist in the Hippocampus after Global Cerebral Ischemia: Implications for Neuronal Self Defense

Abstract

Background: G-protein-Coupled Estrogen Receptor (GPER/GPR30) is a novel membrane-associated estrogen receptor that can induce rapid kinase signaling in various cells. Activation of GPER can prevent hippocampal neuronal cell death following transient global cerebral ischemia (GCI), although the mechanisms remain unclear. In the current study, we sought to address whether GPER activation exerts potent anti-inflammatory effects in the rat hippocampus after GCI as a potential mechanism to limit neuronal cell death. Methods: GCI was induced by four-vessel occlusion in ovariectomized-female SD rats. Specific agonist G1 or antagonist G36 of GPER was administrated using minipump and antisense oligonucleotide (AS) of interleukin-1β receptor antagonist (IL1RA) was administrated using brain infusion kit. Protein expression of IL1RA, NFkB-P65, phosphorylation of CREB (p-CREB), Bcl2, Cleaved-caspase 3 and microglial markers Iba1, CD11b, as well as inflammasome components NLRP3, ASC, Cleaved-caspase 1, and Cle-IL1β in the hippocampal CA1 region were investigated by Immunofluorescent staining and Western blot analysis. The Duo-Link II in situ proximity ligation assay (PLA) was performed to detect the interaction between NLRP3 and ASC. Immunofluorescent staining for NeuN and TUNEL analysis were used to analyze neuronal survival and apoptosis, respectively. We performed Barnes maze and Novel object tests to compare the cognitive function of the rats. Results: The results showed that G1 attenuated GCI-induced elevation of Iba1 and CD11b in the hippocampal CA1 region at 14d reperfusion, and this effect was blocked by G36. G1 treatment also markedly decreased expression of the NLRP3-ASC-Caspase 1 inflammasome and IL1β activation, as well as downstream NFkB signaling, the effects reversed by G36 administration. Intriguingly, G1 caused a robust elevation in neurons of a well-known endogenous anti-inflammatory factor IL1RA, which was reversed by G36 treatment. G1 also enhanced p-CREB level in the hippocampus, a transcription factor known to enhance expression of IL1RA. Finally, in vivo IL1RA-AS abolished the anti-inflammatory, neuroprotective and anti-apoptotic effects of G1 after GCI, and reversed the cognitive-enhancing effects of G1 at 14d after GCI. Conclusions: Taken together, the current results suggest that GPER preserves cognitive function following GCI in part by exerting anti-inflammatory effects and enhancing the defense mechanism of neurons by upregulating IL1RA.

The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease

“…A recently published study shows that GPER activation upregulates interleukin-1 receptor antagonism in the hippocampus after GCI and thus limits ischemic cell death [143]. Importantly, this study suggests that GPER preserves cognitive function following GCI via enhancing the anti-inflammatory defense mechanism of neurons by upregulating interleukin-1β receptor antagonist (IL1RA) [143].…”

“…Subsequently studies reported that GPER activation via G1 administration could rapidly activate PI3K-Akt and MEK-ERK, which are rapid kinase signaling pathways in the hippocampus, and exert strong neuroprotection against global cerebral ischemia (GCI) [71,137,142]. A recently published study shows that GPER activation upregulates interleukin-1 receptor antagonism in the hippocampus after GCI and thus limits ischemic cell death [143]. Importantly, this study suggests that GPER preserves cognitive function following GCI via enhancing the anti-inflammatory defense mechanism of neurons by upregulating interleukin-1β receptor antagonist (IL1RA) [143].…”

Gonadal Hormones E2 and P Mitigate Cerebral Ischemia-Induced Upregulation of the AIM2 and NLRC4 Inflammasomes in Rats

“…Depending on which receptor the hormones bind to, different cascades with different kinetics can be initiated [ 41 ]. Although there is little literature on the estrogen receptors (ERalpha, ERbeta, and GPR30) for cancer and in connection with NLRP3, their impact on NLRC4 and AIM2 is not described yet [ 42 , 43 ]. In addition, the concentration and temporal administration of both hormones might also influence the detected effects.…”

G protein‐coupled estrogen receptor 1: a novel target to treat cardiovascular disease in a sex‐specific manner?

“…Hypertension is now recognised to have an inflammatory component to its pathophysiology (Drummond et al, 2019) with inflammasomes (Pasqua et al, 2018) and T cells (Dinh et al, 2021; Guzik et al, 2007) playing significant roles. Indeed, GPER has potent anti‐inflammatory effects in the circulation (Sharma et al, 2020) and BP‐regulating organs such as the kidneys (Kurt et al, 2016) and brain (Bai et al, 2020). Although activation of GPER has been shown to have anti‐inflammatory effects on T cells (Brunsing et al, 2013), the antihypertensive effects of GPER activation do not appear to involve an action on T cells in aldosterone‐induced hypertension (Dinh et al, 2021).…”

“…Hence, although there remains to be a great deal of further work to understand these sex‐specific findings, it is plausible that men might benefit from GPER antagonists, whereas postmenopausal women might gain protection from GPER agonists administered for the acute treatment of ischaemic stroke. Neuroprotective effects of GPER could involve antiapoptotic actions (Bai et al, 2020; Broughton et al, 2014; Han et al, 2019; Rzemieniec et al, 2015; Tang et al, 2014).…”