Physical contact between lipopolysaccharide and Toll-like receptor 4 revealed by genetic complementation

Some mammalian species show an ability to discriminate between different li popolysaccharide (LPS) partial structures (for example, lipid A and its con gener LA-14-PP, which lacks secondary acyl chains), whereas others do not. Using a novel genetic complementation system involving the transduction of immortalized macrophages from genetically unresponsive C3H/HeJ mice, we now have shown that the species-dependent discrimination between intact LPS an d tetra-acyl LPS partial structures is fully attributable to the species or igin of Toll-like receptor 4 (Tlr4), an essential membrane-spanning compone nt of the mammalian LPS sensor. Because Tlr4 interprets the chemical struct ure of an LPS molecule, we conclude that FPS must achieve close physical pr oximity with Tlr4 in the course of signal transduction.