Microglia have both protective and pathogenic properties, while polarization plays a decisive role in their functional diversity. Apart from being an energetic organelle, mitochondria possess biological capabilities of signaling and immunity involving mitochondrial dynamics. The
N-methyl-D-aspartate (
NMDA)-type
glutamate receptor displays excitatory neurotransmission, excitatory neurotoxicity and pro-inflammatory properties in a membrane location- and cell context-dependent manner. In this study, we have provided experimental evidence showing that by acting on mitochondrial dynamics,
NMDA receptors displayed pro-inflammatory properties, while its non-competitive inhibitor
MK801 exhibited anti-inflammatory potential in
Lipopolysaccharide (LPS)-challenged BV-2 microglia cells. LPS stimulation increased the
protein phosphorylation of cells regarding their
NMDA receptor component subunits and
Calcium/Calmodulin-dependent Protein Kinase II (
CaMKII), along with mobilizing intracellular
calcium. Additionally, parallel changes occurred in the activation of
Transforming Growth Factor-β (TGF-β)-Activated
Kinase 1 (TAK1), NF-κB p65 and NF-κB
DNA binding activity, acquisition of pro-inflammatory M1 polarization and expression of pro-inflammatory
cytokines. LPS-treated cells further displayed signs of
mitochondrial dysfunction with higher expressions of the active form of
Dynamin-Related
Protein 1 (Drp1),
NADPH Oxidase-2 (NOX2) expression and the generation of
DCFDA-/
MitoSOX-sensitive
Reactive Oxygen Species (ROS).
NMDA receptor blockade by
MK801, along with
CaMKII inhibitor
KN93, Drp1 inhibitor
Mdivi-1 and
antioxidant apocynin alleviated LPS-induced pro-inflammatory changes. Other than the reported
CaMKII/TAK1/NF-κB axis, our in vitro study revealed the
CaMKII/Drp1/ROS/NF-κB axis being an alternative cascade for shaping pro-inflammatory phenotypes of microglia upon LPS stimulation, and
MK801 having the potential for inhibiting microglia activation and any associated inflammatory damages.