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.

Neutrophil–Lymphocyte Ratio and Perihematomal Edema Growth in Intracerebral Hemorrhage

“…11 Additionally, recent evidence also suggests that astrocytes shed extracellular vesicles which regulate peripheral leukocyte response in response to brain inflammation. 12 Since inflammation is mainly responsible for PHE evolution 4 , we believe peripheral leukocyte count may aid in stratifying the risk of PHE growth at the time of presentation.…”

Brain–Heart Interaction

“…In addition, damaged endothelial cells and astrocytes at the site of inflammation can shed extracellular vesicles that rapidly cross the BBB and enter the bloodstream 96 . Upon reaching peripheral organs such as the liver, the protein and microRNA (miR) cargo of these endothelial cell and astrocyte derived extracellular vesicles regulate acute cytokine response and mediate trafficking of peripheral immune cells to injured brain tissue 96 . Extracellular vesicles are emerging as intrinsic communication mediators between the brain and immune system 96 .…”

“…Upon reaching peripheral organs such as the liver, the protein and microRNA (miR) cargo of these endothelial cell and astrocyte derived extracellular vesicles regulate acute cytokine response and mediate trafficking of peripheral immune cells to injured brain tissue 96 . Extracellular vesicles are emerging as intrinsic communication mediators between the brain and immune system 96 . The role of microvesicles (MVs) and miR as mediators of brain damage induced heart dysfunction is discussed in detail later in this review.…”

Proceedings of the 2017 ISEV symposium on “HIV, NeuroHIV, drug abuse, & EVs”

“…The underlying mechanism(s) by which plasma EVs affect the brain and, in turn, contribute to the progression of HIV-1 and/or manifest symptoms of drug abuse, however, have not been well understood. Studies by Dickens et al have demonstrated that EVs shed from astrocytes in response to interleukin-1β (IL-1β) can rapidly cross the blood-brain barrier (BBB) and enter the peripheral circulation and the liver, leading to regulation of expression of inflammatory cytokines via suppression of PPARα, finally promoting the transmigration of leukocytes into the CNS (Dickens et al 2017). This study underscores the role of astrocytic EVs as important mediators of communication between the brain and peripheral immune system and as pivotal regulators of immune response within the CNS (Dickens et al 2017).…”

“…Collectively, presentations by experts in the field of NeuroHIV and drug abuse reported substantial accomplishments in the EV field ranging from improved isolation methods, characterization, composition, functions, and application of EVs (DeMarino et al 2017; Dickens et al 2017; Gardiner et al 2016; Hu et al 2016; Konadu et al 2016; Sampey et al 2014; Tang et al 2016; Witwer et al 2013; Yelamanchili et al 2015). The satellite symposium brought together leaders in the field to share their most recent findings and insights.…”