Research ArticlePhysiology

Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions

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Sci. Signal.  04 Apr 2017:
Vol. 10, Issue 473, eaai7696
DOI: 10.1126/scisignal.aai7696

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An astrocyte “call to arms” after brain injury

Brain injuries, such as stroke, physical trauma, and inflammation, stimulate the infiltration of peripheral immune cells that may cause persistent, secondary tissue damage that can impair patient recovery. Using a mouse model of inflammatory brain injury, Dickens et al. found that astrocytes at the site of inflammation released vesicles carrying proteins, RNAs, and microRNAs into the circulation. When these vesicles reached the liver, they stimulated the secretion of cytokines that mobilized peripheral immune cells to infiltrate the brain. Inhibiting this long-range communication between the brain and the liver might accelerate and improve recovery from brain injuries.

Abstract

Brain injury induces a peripheral acute cytokine response that directs the transmigration of leukocytes into the brain. Because this brain-to-peripheral immune communication affects patient recovery, understanding its regulation is important. Using a mouse model of 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-1β (IL-1β) rapidly entered into peripheral circulation and promoted the transmigration of leukocytes through modulation of the peripheral acute cytokine response. Bioinformatic analysis of the protein and microRNA cargo of EVs identified peroxisome proliferator–activated receptor α (PPARα) 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 PPARα, resulting in the increase of nuclear factor κB (NF-κB) activity that triggered the production of cytokines in liver. These findings expand our 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.

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