title: Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions.
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.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Alex M
authors.identifier: http://orcid.org/0000-0002-3178-8449
authors.initials: AM
authors.lastname: Dickens
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Luis B
authors.identifier: http://orcid.org/0000-0003-2605-1378
authors.initials: LB
authors.lastname: Tovar-Y-Romo
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Seung-Wan
authors.identifier: http://orcid.org/0000-0003-1702-8459
authors.initials: SW
authors.lastname: Yoo
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Amanda L
authors.identifier: http://orcid.org/0000-0002-4754-8634
authors.initials: AL
authors.lastname: Trout
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Mihyun
authors.identifier: http://orcid.org/0000-0001-8961-3396
authors.initials: M
authors.lastname: Bae
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Marlene
authors.identifier: http://orcid.org/0000-0001-7428-5270
authors.initials: M
authors.lastname: Kanmogne
authors.affiliation: Departments of Pathology, Microbiology, and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Bezawit
authors.initials: B
authors.lastname: Megra
authors.affiliation: Departments of Pathology, Microbiology, and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Dionna W
authors.identifier: http://orcid.org/0000-0001-5029-2628
authors.initials: DW
authors.lastname: Williams
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Kennith W
authors.identifier: http://orcid.org/0000-0003-1664-4233
authors.initials: KW
authors.lastname: Witwer
authors.affiliation: Department of Neuroscience, Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Mar
authors.identifier: http://orcid.org/0000-0003-1583-1643
authors.initials: M
authors.lastname: Gacias
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Nino
authors.identifier: http://orcid.org/0000-0001-6826-1459
authors.initials: N
authors.lastname: Tabatadze
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Robert N
authors.identifier: http://orcid.org/0000-0002-3096-4754
authors.initials: RN
authors.lastname: Cole
authors.affiliation: Department of Neuroscience, Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Patrizia
authors.identifier: http://orcid.org/0000-0002-4785-9264
authors.initials: P
authors.lastname: Casaccia
authors.affiliation: Departments of Pathology, Microbiology, and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Joan W
authors.identifier: http://orcid.org/0000-0003-0635-4072
authors.initials: JW
authors.lastname: Berman
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
authors.forename: Daniel C
authors.identifier: http://orcid.org/0000-0003-1380-6655
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. nhaughe1@jhmi.edu.|Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Norman J
authors.identifier: http://orcid.org/0000-0001-5194-4122
authors.initials: NJ
authors.lastname: Haughey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D057688:Transcellular Cell Migration / Q000187:drug effects / Q000235:genetics
chemical_list: D002518:Ceramides; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase