2. Academic Validation
  3. Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions

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

  • Sci Signal. 2017 Apr 4;10(473):eaai7696. doi: 10.1126/scisignal.aai7696.
Alex M Dickens 1,  Luis B Tovar-Y-Romo 1,  Seung-Wan Yoo 1,  Amanda L Trout 1,  Mihyun Bae 1,  Marlene Kanmogne 1,  Bezawit Megra 2,  Dionna W Williams 2,  Kennith W Witwer 3,  Mar Gacias 4,  Nino Tabatadze 1,  Robert N Cole 5,  Patrizia Casaccia 4,  Joan W Berman 2,  Daniel C Anthony 6,  Norman J Haughey 7 8
Affiliations

Affiliations

  • 1 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 2 Departments of Pathology, Microbiology, and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 3 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 4 Department of Neuroscience, Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 5 Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 6 Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
  • 7 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. nhaughe1@jhmi.edu.
  • 8 Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
PMID: 28377412 DOI: 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-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.

Figures