A1 Refereed original research article in a scientific journal
Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions
Authors: Dickens AM, Tovar-y-Romo LB, Yoo SW, Trout AL, Bae M, Kanmogne M, Megra B, Williams DW, Witwer KW, Gacias M, Tabatadze N, Cole RN, Casaccia P, Berman JW, Anthony DC, Haughey NJ
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Publication year: 2017
Journal: Science Signaling
Journal name in source: SCIENCE SIGNALING
Journal acronym: SCI SIGNAL
Article number: ARTN eaai7696
Volume: 10
Issue: 473
Number of pages: 12
ISSN: 1945-0877
eISSN: 1937-9145
DOI: https://doi.org/10.1126/scisignal.aai7696
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-1 beta (IL-1 beta) 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 a (PPARa) 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 nuclear factor kappa B (NF-kappa B) 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.
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-1 beta (IL-1 beta) 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 a (PPARa) 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 nuclear factor kappa B (NF-kappa B) 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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