Wednesday, November 4, 2009: 11:00 AM
Kohlberg (Camino Real Hotel)
Inflammation mediated by TNF-a and the associated neuronal apoptosis characterizes a number of neurologic disorders. Macrophages and microglial cells are believed the major source of TNF-a in the central nervous system. Here, we show that suppression of TNF-a by targeted delivery of siRNA to macrophage/microglial cells dramatically reduces LPS-induced neuroinflammation and neuronal apoptosis in vivo. Because macrophage/microglia express the nicotinic acetylcholine receptor (AchR) on their surface, we used a short AchR-binding peptide derived from the Rabies virus glycoprotein as a targeting ligand. This peptide was fused to nona-D-arginine residues (RVG-9dR) to enable siRNA binding. RVG-9dR was able to deliver siRNA to induce gene silencing in macrophages and microglia cells from wild type, but not AchR-deficient mice, confirming targeting specificity. Treatment with anti-TNF-a siRNA complexed to RVG-9dR achieved efficient silencing of LPS-induced TNF-a production by primary macrophages and microglia cells in vitro. Moreover, intravenous injection with RVG-9dR-complexed siRNA in mice reduced the LPS-induced TNF-a levels in blood as well as in the brain, leading to a significant reduction in neuronal apoptosis. These results demonstrate that RVG-9dR provides a tool for siRNA delivery to macrophages and microglia and that suppression of TNF-a can potentially be used to suppress neuroinflammation in vivo.