Identification of a novel mechanism of blood–brain communication during peripheral inflammation via choroid plexus‐derived extracellular vesicles

Here, we identified release of extracellular vesicles (EVs) by the choroid plexus epithelium (CPE) as a new mechanism of blood–brain communication. Systemic inflammation induced an increase in EVs and associated pro‐inflammatory miRNAs, including miR‐146a and miR‐155, in the CSF. Interestingly, this was associated with an increase in amount of multivesicular bodies (MVBs) and exosomes per MVB in the CPE cells. Additionally, we could mimic this using LPS‐stimulated primary CPE cells and choroid plexus explants. These choroid plexus‐derived EVs can enter the brain parenchyma and are taken up by astrocytes and microglia, inducing miRNA target repression and inflammatory gene up‐regulation. Interestingly, this could be blocked in vivo by intracerebroventricular (icv) injection of an inhibitor of exosome production. Our data show that CPE cells sense and transmit information about the peripheral inflammatory status to the central nervous system (CNS) via the release of EVs into the CSF, which transfer this pro‐inflammatory message to recipient brain cells. Additionally, we revealed that blockage of EV secretion decreases brain inflammation, which opens up new avenues to treat systemic inflammatory diseases such as sepsis. Synopsis New mechanism of blood–brain communication by the choroid plexus epithelial cells: uniquely positioned between blood and brain, choroid plexus epithelial cells release extracellular vesicles upon peripheral inflammation and transfer a pro‐inflammatory message to the brain. Systemic inflammation induces the release of miRNA‐containing extracellular vesicles by the choroid plexus epithelium cells into the cerebrospinal fluid. Choroid plexus epithelium‐derived EVs are able to cross the ependymal cells lining the ventricles and reach the brain parenchyma, and they are taken up by astrocytes and microglia. The choroid plexus epithelium‐derived EVs transfer a pro‐inflammatory signal to the brain. Graphical Abstract New mechanism of blood–brain communication by the choroid plexus epithelial cells: uniquely positioned between blood and brain, choroid plexus epithelial cells release extracellular vesicles upon peripheral inflammation and transfer a pro‐inflammatory message to the brain.