The Emerging Role of the GPR109A (HCA2/PUMA‐G) Receptor in Regulating Macrophage Function

The objective of this study is to investigate the novel role of GPR109A (HCA2/PUMA‐G) and its ligand nicotinic acid in regulating macrophage function. Gpr109a expression in the RAW264.7 murine macrophage cell line is strongly induced by lipopolysaccharide (LPS) treatment and correlates with the expression of TNF‐α□ Treatment with 300 μM nicotinic acid (reported EC50 3 μM, peak plasma concentration 50–300 μM), significantly inhibited TNF‐α, IL‐6, IL‐12p40, and IL‐1β production (P<0.05) in LPS (1ng/ml)‐stimulated wild‐type murine bone marrow‐derived macrophages (BMM) but failed to do so in Gpr109a−/− BMM. Treatment with nicotinic acid reduced nuclear factor κB (NF‐κB) activation levels by 30% in wild‐type BMM 6 hours after LPS stimulation but not in Gpr109a−/− BMM. Nicotinic acid significantly inhibited wild‐type BMM chemotaxis (P<0.001), but had no effect on the chemotaxis of Gpr109a−/−BMM. A significant increase in low‐density lipoprotein (LDL) uptake by both wild‐type (P<0.006) and Gpr109a−/− BMM (P<0.03) in response to LPS was observed, which was significantly suppressed by nicotinic acid in wild‐type BMM (P<0.04) but not in Gpr109a−/− BMM. Our results suggest that the nicotinic acid‐GPR109A axis is a negative regulator of macrophage activation.