Neural immune cell responses to clinically relevant ligands of the niacin receptor (Gpr109a): niacin and monomethyl fumarate

Brown-Lyons, Amy Louise

Abstract

Background: Inflammation is a major driver, and perhaps cause, of neurodegeneration, suggesting neuroimmunomodulation as a therapeutic strategy. Microglia, the primary mediators of neuroinflammation, switch between three activation states [surveillant/unactivated (M0), proinflammatory (M1), anti-inflammatory/pro-repair (M2)], with M1 being associated with worsening pathology, while M2 is associated with reduced severity. Microglia reportedly express Gpr109a, a receptor predicted, but not demonstrated, to reduce M1 and induce M2 phenotype switching. If Gpr109a ligands do reduce M1 and promote M2 microglial activation, this may be therapeutically beneficial. Astrocytes are secondary immunocompetent glial cells, which can express Gpr109a, although most astrocytes are reportedly Gpr109a-. It remains unclear whether Gpr109a ligands induce responses in Gpr109a+ astrocytes.
Methods: Primary rat cortical microglia and astrocyte cultures were assessed for Gpr109a expression, and treated with Gpr109a ligands (niacin, monomethyl fumarate). Controls included nicotinamide (similar metabolic effects to niacin, but without Gpr109a activation) and lipopolysaccharide (LPS, positive inflammatory control). Microglial and astrocyte responses were assessed by marker expression (immunostaining: Arg1, Gpr109a, Iba1, Nox2) and morphometric analyses.
Results: Expression of Gpr109a was demonstrated for rat microglia and astrocytes, with the majority of cells being Gpr109a+. Clear glial responses to Gpr109a ligands were not reproducibly demonstrated for either microglia or astrocytes. For Gpr109a ligands and for LPS, no consistent dose-response effects were seen in expression of Gpr109a, Nox2, Iba1 or Arg1. Morphological measurements showed no consistent responses to Gpr109a ligands or LPS treatment (Cell area, perimeter, Feret’s max/min diameter, aspect ratio, circularity index).
Conclusion: Gpr109a represents a promising target for neuroimmunomodulatory therapies, as clinically approved ligands have good safety profiles, and neural immune cells express Gpr109a. Future studies should employ more sophisticated CNS models, including injury/disease to determine whether Gpr109a ligands may generate beneficial responses in neuroimmune cells already undergoing inflammatory/pathological activation.

• Thesis Type: Thesis
• Deposit Date: Jul 20, 2023
• Publicly Available Date: Jul 20, 2023
• Award Date: 2023-06