Interaction Between Cationic Lipids and Endotoxin Receptors

Abstract

It has been recently demonstrated that diC14-amidine, a cationic lipid, activate cytokine secretion (TNF-alpha, IL-12, IFN-gamma, IP-10) in dendritic cells through a Toll-like Receptor-4-dependent mechanism [Tanaka et al., 2008]. This receptor is involved in the recognition of the bacterial endotoxins (lipopolysaccharides, LPS) and activation of innate immune system. DiC14-amidine could activate this cascade by different mechanism [Lonez et al., 2008].Our first hypothesis is that diC14-amidine interacts with the co-receptor of TLR4, MD-2. DiC14-amidine has 2 acyl chains that mimic LPS acyl chains. Molecular dynamics simulations of the insertion of diC14-amidine in the MD-2 cavity revealed that two amidine molecules do occupy a volume identical to that of one tetra-acylated lipid A molecule, an antagonist of TLR4, in the cavity. A non-exclusive alternative could consist in a modification of the membrane environment of TLR4, upon insertion of cationic lipids in the membrane bilayer. The ability of diC14-amidine liposomes to fuse with cell membranes was demonstrated by confocal microscopy or (FRET) Fluorescence Resonance Energy Transfer measurements. Fusion (lipid mixing) with the cell membrane would be a way to insert cationic lipid in the lipid bilayer of the plasma membrane and to modify the lipid-protein interactions involved in the function of membrane proteins. Biophysical studies (AFM, X-ray scattering) revealed that amidine molecules adopts an interdigitated structure and does not require additional lipids (PE) to be fusogenic. This raises also the question of the role of interdigitated structures in the fusion (lipid mixing) mechanism.ReferencesLonez C, Vandenbranden M, Ruysschaert JM. Prog Lipid Res. 2008. 47(5):340-7.Tanaka T et al. Eur J Immunol. 2008. 38(5):1351-7.