A Game of Molecular Telephone: Macrophage Cells Signal Infection through Exosomes
How do cells talk to one another? Signals sent via cytokine and chemokines activate specific signaling pathways to influence cell activity, but other means of communication can also contribute. A new Infection and Immunity report characterizes one mechanism by which Salmonella-infected macrophage cells alert nearby uninfected macrophage: through intercellular communication via exosomes. These exosomes from infected cells act as molecular telephones, carrying messages that alert uninfected cells to the presence of the intracellular bacterial pathogen.
TEM images of exosomes purified from Salmonella-infected macrophage cells. Source.
Study first author Winnie Hui and senior scientist Mariola Edelmann observed different protein secretion profiles from uninfected and Salmonella-infected macrophages. When they investigated further, they found this was due to the Salmonella both interfering with host secretory pathways as well as changing the contents of exosomes. Exosomes are membrane-bound vesicles that carry cargo and are released from cells (see image, right). These protein, lipid, and carbohydrate cargos differ from those that are released directly into the extracellular environment. Exosomes from macrophage cells can alert and influence the response of nearby immune cells, depending on the cargo they contain.
The exosomes from Salmonella-infected macrophage cells activate the release of TNF-α and other proinflammatory cytokines from nearby uninfected macrophages. The activation was at least partially due to the lipopolysaccharide (LPS), part of the gram-negative bacterial cell envelope, that was incorporated into the exosomes from the infected cells, although protein components were also involved. The strongest TNF-α response came from exosomes containing CD9, a glycoprotein member of the tetraspanin family that may play a role in membrane adhesion, and but also depended on host-side interactions with Toll-like receptors (TLRs) 2 and 4.
The scientists found that exosomes from macrophages infected for as little as 2 hours can activate a proinflammatory response from naïve macrophage cells. This suggests that exosomes can act as an alert system to allow nearby macrophage to quickly respond to the invading microbe. These studies were all done using in vitro or ex vivo cell lines, so the next step to understanding the role of macrophage-derived exosomes will be to move into an animal model of infection.
Bacterial-derived outer membrane vesicles have made their way to clinical use as vaccines, and other microbial membrane vesicles play various roles in disease. This report suggests that host-derived exosomes may also manipulate outcome early in infection, and if that’s the case, we may someday be able to alter macrophage or other host-derived exosomes for potential clinical uses. If macrophage cells use exosomes like telephones to spread molecular messages, we might just tell them what to say.