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.
Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium Department of Medical Protein Research, VIB, Ghent, Belgium Department of Biochemistry, Ghent University, Ghent, Belgium.
Sriram
S
Balusu
Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Elien
E
Van Wonterghem
Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Riet
R
De Rycke
Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Koen
K
Raemdonck
Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Stephan
S
Stremersch
Department of Medical Protein Research, VIB, Ghent, Belgium Department of Biochemistry, Ghent University, Ghent, Belgium.
Kris
K
Gevaert
Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium Department of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Republic of Serbia.
Marjana
M
Brkic
Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Delphine
D
Demeestere
Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Valerie
V
Vanhooren
Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University, Ghent, Belgium.
An
A
Hendrix
Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Claude
C
Libert
Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium roosmarijn.vandenbroucke@irc.vib-ugent.be.
Roosmarijn E
0000-0002-8327-620X
RE
Vandenbroucke
D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000737:chemistry; D002831:Choroid Plexus / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000378:metabolism*; D007155:Immunologic Factors / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000032:analysis; D009924:Organ Culture Techniques
D007155:Immunologic Factors; D008070:Lipopolysaccharides; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C532623:Mirn155 microRNA, mouse
blood–brain barrier; choroid plexus; exosomes; extracellular vesicles; sepsis