Innate Immune Recognition of Bacterial Lipopolysaccharide: Dependence on Interactions with Membrane Lipids and Endocytic Movement

Lipopolysaccharide ([LPS], an endotoxin) from most bacterial species provokes a strong inflammatory response in naive animals. LPS from Rhodobacter sphaeroides (RsLPS) has a relatively small hydrophobic region and does not stimulate cells or animals but instead acts as antagonist of LPS action. Here, we show that the activity of RsLPS is transformed from antagonist to full agonist by the addition of chlorpromazine (CPZ) and other cationic membrane-active agents. In addition, while LPS is rapidly transported from the plasma membrane to an intracellular site, we find that RsLPS is not transported but instead remains in the cell periphery. Addition of CPZ also reverses this behavior, causing RsLPS to be transported to a perinuclear site. The data suggest that the interaction of LPS with membrane lipids is influenced by membrane-modifying agents such as CPZ, and these interactions dictate both its intracellular transport and its ability to stimulate cellular responses.