Membrane phospholipids activate the inflammatory response in macrophages by various mechanisms

Exosomes, which are small membrane-encapsulated particles derived from all cell types, are emerging as important mechanisms for intercellular communication. In addition, exosomes are currently envisioned as potential carriers for the delivery of drugs to target tissues. The natural population of exosomes is very variable due to the limited amount of cargo components present in these small vesicles. Consequently, common components of exosomes may play a role in their function. We have proposed that membrane phospholipids could be a common denominator in the effect of exosomes on cellular functions. In this regard, we have previously shown that liposomes made of phosphatidylcholine (PC) or phosphatidylserine (PS) induced a robust alteration of macrophage (M phi) gene expression. We herewith report that these two phospholipids modulate gene expression in M phi s by different mechanisms. PS alters cellular responses by the interaction with surface receptors, particularly CD36. In contrast, PC is captured by a receptor-independent process and likely triggers an activity within endocytic vesicles. Despite this difference in the capture mechanisms, both lipids mounted similar gene expression responses. This investigation suggests that multiple mechanisms mediated by membrane phospholipids could be participating in the alteration of cellular functions by exosomes. Phosphatidylcholine (PC) and phosphatidylserine (PS), two natural phospholipids found in plasma membranes and the membrane of exosomes, induce the NF-kappa B-mediated expression of inflammatory cytokines in macrophages by different mechanisms of activation. Palmitoyl-2-oleoyl-PS (POPS) liposomes preferentially associate with CD36, a member of the class B scavenger receptor family, whereas palmitoyl-2-oleoyl-PC (POPC) liposomes are captured via pinocytosis. Once internalized, both phospholipids trigger the phosphorylation and nuclear translocation of the NF-kappa B subunit p65, which leads to the expression of various inflammatory mediators.image