MGLUR5 ACTIVATION INHIBITS MICROGLIAL ASSOCIATED INFLAMMATION AND NEUROTOXICITY

Microglia play a crucial role in the brain's inflammatory response to injury and disease. While various metabotropic glutamate receptors (mGluRs) have been identified on these immune cells, their functional impact on neuroinflammation remains debated. This study investigates whether the mGluR5 receptor is expressed in microglia and whether its activation can modulate the inflammatory response and resulting neurotoxicity.

Researchers utilized primary rat microglial cultures, as well as microglia derived from mGluR5 knockout and wild-type mice. They used immunocytochemistry and Western blot analyses to confirm the presence of mGluR5 on the microglial cell surface. To examine the functional role of the receptor, the team treated microglia with the selective mGluR5 agonist CHPG prior to stimulating them with lipopolysaccharide (LPS), a common inflammatory trigger. They then measured markers of activation such as nitric oxide (NO), reactive oxygen species (ROS), and tumor necrosis factor-alpha (TNFα), and evaluated microglial-induced neurotoxicity in co-cultures with neurons. Further experiments used specific inhibitors to delineate the intracellular signaling pathways involved.

The researchers found that mGluR5 is robustly expressed in microglia, whereas mGluR1 expression is negligible. Treatment with the mGluR5 agonist CHPG significantly suppressed the production of NO, ROS, and TNFα in LPS-stimulated microglia. This treatment also reduced the capacity of activated microglia to damage neighboring neurons. These protective effects were absent in microglia from mGluR5 knockout mice and were reversed by selective mGluR5 antagonists, confirming that the benefits are specifically mediated by mGluR5. Mechanistic investigations revealed that CHPG triggers the Gαq-protein signal transduction pathway, specifically involving phospholipase C (PLC) and protein kinase C (PKC) activity, rather than the cAMP pathway.