Astrocyte-Derived Estrogen Regulates Reactive Astrogliosis and is Neuroprotective following Ischemic Brain Injury

Abstract

Expression of the 17b-estradiol (E2) synthesis enzyme aromatase is highly upregulated in astrocytes following brain injury. However, the precise role of astrocyte-derived E2 in the injured brain remains unclear. In the current study, we generated a glial fibrillary acidic protein (GFAP) promoter-driven aromatase knock-out (GFAP-ARO-KO) mouse model to deplete astrocyte-derived E2 in the brain and determine its roles after global cerebral ischemia (GCI) in male and female mice. GFAP-ARO-KO mice were viable and fertile, with normal gross brain structure, normal morphology, intensity and distribution of astrocytes, normal aromatase expression in neurons, and normal cognitive function basally. In contrast, after GCI, GFAP-ARO-KO mice: (1) lacked the normal elevation of astrocyte aromatase and hippocampal E2 levels; (2) had significantly attenuated reactive astrogliosis; and (3) displayed enhanced neuronal damage, microglia activation, and cognitive deficits. RNAsequencing (RNA-seq) analysis revealed that the ischemic GFAP-ARO-KO mouse hippocampus failed to upregulate the "A2" panel of reactive astrocyte genes. In addition, the JAK-STAT3 pathway, which is critical for the induction of reactive astrogliosis, was significantly downregulated in the GFAP-ARO-KO hippocampus following GCI. Finally, exogenous E2 administration fully rescued the compromised JAK-STAT3 pathway and reactive astrogliosis, and reversed the enhanced neuronal damage and microglial activation in the GFAP-ARO-KO mice after GCI, suggesting that the defects in the KO mice are because of a loss of E2 rather than an increase in precursor androgens. In conclusion, the current study provides novel genetic evidence for a beneficial role of astrocyte-derived E2 in reactive astrogliosis, microglial activation, and neuroprotection following an ischemic injury to the brain.

Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

“…In this study, the direct involvement of the mitochondrial estrogen receptor beta (mtERβ) in the activation of the mitochondrial defense antioxidant and anti-apoptotic activities is demonstrated. Accumulated evidence substantiates the regulatory and protective actions of estrogens on the brain, affecting both glial and neuronal physiology [ 17 , 21 , 32 , 33 , 34 , 35 ]. Particularly, the regulation of neuronal mitochondrial functions by estrogen is widely accepted [ 36 , 37 ].…”

Flaxseed Oil Attenuates Trimethyltin-induced Neurodegeneration via Down-regulation of Inflammatory Activity of Astrocytes

“…Since E2 and ERα are direct regulators of GFAP transcription and ultimately major contributors to astrocyte activation (Arimoto et al 2013;Wang et al 2020), the possible modulation of hippocampal local E2 production was also explored through the analysis of the expression levels of Arom (the key enzyme involved in E2 biosynthesis) and ERα, which acts as transcription factor towards GFAP promor sequence (Arimoto et al 2013). For all target genes, signi cant effects of TMT, FSO treatment and the interaction were obtained: Arom-mRNA -the effect of TMT (F(1,15) = 8.52; P = 0.0106), FSO treatment (F(1,15) = 9.28; P = 0.0081) and the interaction (F(1,15) = 8.065; P = 0.0124); for ERα-mRNA -the effect of TMT (F(1, 16) = 6.61; P < 0.05), treatment (F(1, 16) = 10.92; P < 0.01) and interaction (F(1, 16) = 5.962; P < 0.05).…”

“…Also, TMT robustly elevate complement C3 (C3) which is highly up-regulated in A1-like reactive astrocytes (Zamanian et al 2012; Liddelow and Barres 2017; Dragić et al 2020Dragić et al , 2021. Furthermore, such activated astrocytes probably precedes microglial activation (Röhl and which play key role in the regulation of reactive astrogliosis (Wang et al 2020). Collectively, astrocyte activation and neuroin ammation contribute to the pathogenesis of TMT-induced cognitive decline and neurotoxicity, and speci c prophylactic/therapeutic strategies actively targeting activated/proin ammatory astrocytes might be of great relevance.…”

“…Speci cally, TMT induces up-regulation of NF-κB and its target proin ammatory genes, such as interleukin (IL)-1β, IL-10, IL-6, tumor necrosis factor-α (TNF-α) that was limited to activated astrocytes (O'Callaghan et al 2014; Haim et al 2015;Dragić et al 2020Dragić et al , 2021. Also, TMT robustly elevate complement C3 (C3) which is highly up-regulated in A1-like reactive astrocytes which play key role in the regulation of reactive astrogliosis (Wang et al 2020). Collectively, astrocyte activation and neuroin ammation contribute to the pathogenesis of TMT-induced cognitive decline and neurotoxicity, and speci c prophylactic/therapeutic strategies actively targeting activated/proin ammatory astrocytes might be of great relevance.…”

The neuroprotective effect of meloxicam in a transient ischemia model involves an increase in axonal sprouting but a decrease in new neuron formation after 7 days of reperfusion

“…Astrocyte involvement in the local inflammatory response after ischemia is widely described [46][47][48]. The formation of the glial scar limits the extent of the damage, but also interferes with the regenerative response attempts by secreting inhibitory factors [49,50].…”