IMR Press / JIN / Volume 23 / Issue 2 / DOI: 10.31083/j.jin2302026
Open Access Original Research
Metabotropic Glutamate Receptor 8 Suppresses M1 Polarization in Microglia by Alleviating Endoplasmic Reticulum Stress and Mitochondrial Dysfunction
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1 Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
2 Department of Intensive Care Unit, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
*Correspondence: (Yongjun Chen)
These authors contributed equally.
J. Integr. Neurosci. 2024, 23(2), 26;
Submitted: 8 May 2023 | Revised: 25 July 2023 | Accepted: 9 August 2023 | Published: 2 February 2024
Copyright: © 2024 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: Microglia-mediated neuroinflammation is a hallmark of neurodegeneration. Metabotropic glutamate receptor 8 (GRM8) has been reported to promote neuronal survival in neurodegenerative diseases, yet the effect of GRM8 on neuroinflammation is still unclear. Calcium overload-induced endoplasmic reticulum (ER)-mitochondrial miscommunication has been reported to trigger neuroinflammation in the brain. The aim of this study was to investigate putative anti-inflammatory effects of GRM8 in microglia, specifically focusing on its role in calcium overload-induced ER stress and mitochondrial dysfunction. Methods: BV2 microglial cells were pretreated with GRM8 agonist prior to lipopolysaccharide administration. Pro-inflammatory cytokine levels and the microglial polarization state in BV2 cells were then quantified. Cellular apoptosis and the viability of neuron-like PC12 cells co-cultured with BV2 cells were examined using flow cytometry and a Cell Counting Kit-8, respectively. The concentration of cAMP, inositol-1,4,5-triphosphate receptor (IP3R)-dependent calcium release, ER Ca2+ concentration, mitochondrial function as reflected by reactive oxygen species levels, ATP production, mitochondrial membrane potential, expression of ER stress-sensing protein, and phosphorylation of the nuclear factor kappa B (NF-κB) p65 subunit were also quantified in BV2 cells. Results: GRM8 activation inhibited pro-inflammatory cytokine release and shifted microglia polarization towards an anti-inflammatory-like phenotype in BV2 cells, as well as promoting neuron-like PC12 cell survival when co-cultured with BV2 cells. Mechanistically, microglial GRM8 activation significantly inhibited cAMP production, thereby desensitizing the IP3R located within the ER. This process markedly limited IP3R-dependent calcium release, thus restoring mitochondrial function while inhibiting ER stress and subsequently deactivating NF-κB signaling. Conclusions: Our results indicate that GRM8 activation can protect against microglia-mediated neuroinflammation by attenuating ER stress and mitochondrial dysfunction, and that IP3R-mediated calcium signaling may play a vital role in this process. GRM8 may thus be a potential target for limiting neuroinflammation.

metabotropic glutamate receptor 8
endoplasmic reticulum stress
mitochondrial function
M1/M2 polarization
20201910/key projects of Hunan Provincial Health and Health Commission
Fig. 1.
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