Inflammatory Cytokine, IL-1β, Regulates Glial Glutamate Transporter via microRNA-181a in vitro

Abstract

Glutamate overload triggers synaptic and neuronal loss that potentially contributes to neurodegenerative diseases including Alzheimer's disease (AD). Glutamate clearance and regulation at synaptic clefts is primarily mediated by glial glutamate transporter 1 (GLT-1). We determined that inflammatory cytokines significantly upregulated GLT-1 through microRNA-181a-mediated post-transcriptional modifications. Unveiling the key underlying mechanisms modulating GLT-1 helps better understand its physiological and pathological interactions with cytokines. Primary murine astrocyte and neuron co-culture received 20 ng/mL IL-1β, TNF-α, or IL-6 for 48 h. Soluble proteins or total RNA were extracted after treatment for further analyses. Treatment with inflammatory cytokines, IL-1β and TNF-α, but not IL-6, significantly increased GLT-1 steady-state levels (p≤0.05) without affecting mRNA levels, suggesting the cytokine-induced GLT-1 was regulated through post-transcriptional modifications. Among the candidate microRNAs predicted to modulate GLT-1, only microRNA-181a was significantly decreased following the IL-1β treatment (p≤0.05). Co-treatment of microRNA-181a mimic in IL-1β-treated primary astrocytes and neurons effectively blocked the IL-1β-induced upregulation of GLT-1. Lastly, we attempted to determine the link between GLT-1 and microRNA-181a in human AD brains. A significant reduction of GLT-1 was found in AD hippocampus tissues, and the ratio of mature microRNA-181a over primary microRNA-181a had an increasing tendency in AD. MicroRNA-181a controls rapid modifications of GLT-1 levels in astrocytes. Cytokine-induced inhibition of microRNA-181a and subsequent upregulation of GLT-1 may have physiological implications in synaptic plasticity while aberrant maturation of microRNA-181a may be involved in pathological consequences in AD.

Neuroinflammation, Sleep, and Circadian Rhythms

“…TNF-α can also increase the post-synaptic membrane ( Beattie et al., 2002 ). Both TNF-α and IL-1β increase intracellular and extracellular glutamate levels ( Ye et al., 2013 ; Zumkehr et al., 2018 ). TNF-α and IL-1β can also increase the glial glutamate transporter 1 which can facilitate glutamatergic transmission.…”

“…TNF-α and IL-1β can also increase the glial glutamate transporter 1 which can facilitate glutamatergic transmission. ( Ye et al., 2013 ; Zumkehr et al., 2018 ) IL-1β also modulates AMPA receptor expression and phosphorylation in neurons ( Lai et al., 2006 ). Nevertheless, multiple mechanisms are likely involved of how cytokines alter molecules that can alter sleep and interact with circadian biology and indicative of the necessity of sleep.…”

The emerging role of noncoding RNAs in neuroinflammation: Implications in pathogenesis and therapeutic approaches

“…Indeed, the spatially‐limited transient increase of cytokines such as IL‐1β induces the expression of glial glutamate transporter 1 (GLT1) as an important neurotransmitter transporter protein during physiological conditions. Therefore, this study suggested that IL‐1β can inhibit miR‐181a and thus, up‐regulate its target gene, GLT1 (Zumkehr et al, 2018). Another study showed a lower expression of miR‐186 in AD rat brains associated with higher levels of IL‐2 (D. M. Wu et al, 2018).…”

Involvement of Astrocytes and microRNA Dysregulation in Neurodegenerative Diseases: From Pathogenesis to Therapeutic Potential

“…Glial glutamate transporter 1 (GLT-1) contributes to the clearance and regulation of glutamate at synaptic clefts. An increase in miR-181a downregulated some synaptic proteins that are involved in plasticity in a 3xTg-AD mouse model and had a negative regulatory relationship with GLT-1, suggesting that miR-181a is a key mediator of the plasticity of glutamatergic synapses by controlling the expression of synaptic proteins, including GLT-1, in astrocytes (Zumkehr et al, 2015 , 2018 ).…”