miRNA content of extracellular vesicles released from astrocytes upon stimulation of IL-1beta and control

Brain injury induces a peripheral acute cytokine response (ACR) that directs the transmigration of leukocytes into brain. This brain-to-peripheral immune communication affects patient recovery, thus understanding how it is regulated is important. Contrary to expectations, it is not regulated by sympathetic innervation. Using a mouse model of an inflammatory brain injury, we set out to find a soluble mediator for this phenomenon. We found that extracellular vesicles (EVs) shed from astrocytes in response to intracerebral injection of interleukin-1b (IL-1b) rapidly entered into peripheral circulation and promoted the transmigration of leukocytes through modulation of the peripheral ACR. Bioinformatic interrogation of the protein and miRNA cargo of EVs identified Peroxisome proliferator-activated receptor-α (PPAR-a)  as a primary molecular target of astrocyte-shed EVs. We confirmed in mice that astrocytic EVs promoted the transmigration of leukocytes into the brain by inhibiting PPARa resulting in the increase of NF-κB activity thus, triggering the production of cytokines in liver. These findings expand our basic understanding of the mechanisms regulating communication between the brain and peripheral immune system, and identify astrocytic EVs as a molecular regulator of the immunological response to inflammatory brain damage. This study characterised the miRNA content of extracellular vesicles released from cultured astrocytes when stimulated with IL-1beta. The control exosomes were generated by collecting all particles released over a 24h period.