Dataset Information

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

ABSTRACT: Brain injury induces a peripheral acute cytokine response (ACR) that directs the transmigration of leukocytes into brain. This brain-to-peripheral immune communication affects patient recovery, thus understanding how it is regulated is important. Contrary to expectations it is not regulated by sympathetic innervation. Using a mouse model of an inflammatory brain injuryXXX , we set out to find a soluble mediator for this phenomenon. We found that extracellular vesicles (EVs) shed from astrocytes in response to intracerbral injection of interleukin-1 (IL-1) rapidly entered into peripheral circulation and promoted the transmigration of leukocytes through modulation of the peripheral ACR. Bioinformatic interrogation of the protein and miRNA cargo of EVs identified Peroxisome proliferator-activated receptor-α (PPAR-α) 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 modulating inhibiting PPAR and presumably subsequentlyresulting in the increase of NF-κB activity thus, triggering the production of cytokines in liver. These findings expand our basic 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Primary Cell, Astrocyte Of The Cerebral Cortex, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Alex Dickens

LAB HEAD: Norman J Haughey

PROVIDER: PXD006087 | Pride | 2018-10-26

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Dickens_proten_data.sf3	Other
	LD-CS-141106_HaughyN_Control.raw	Raw
	LD-CS-141106_HaughyN_IlBeta.raw	Raw
	Samples_Report_for_Dickens_proten_data.xls	Xls

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

Dickens Alex M AM Tovar-Y-Romo Luis B LB Yoo Seung-Wan SW Trout Amanda L AL Bae Mihyun M Kanmogne Marlene M Megra Bezawit B Williams Dionna W DW Witwer Kennith W KW Gacias Mar M Tabatadze Nino N Cole Robert N RN Casaccia Patrizia P Berman Joan W JW Anthony Daniel C DC Haughey Norman J NJ

Science signaling 20170404 473

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 int ...[more]

PMID: 28377412

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Project description:The blood-brain barrier (BBB) dynamically controls and maintains a precisely balanced brain microenvironment necessary for reliable functioning. It is made up of highly specialized endothelial cells (ECs) in the lining of the vascular wall. These ECs are surrounded by the basal lamina, astrocytic perivascular endfeet, pericytes, microglia and neuronal processes that have been shown to contribute to barrier function1. In essence, the brain endothelium limits both transcellular and paracellular passage of cells and molecules into the central nervous system (CNS). Transcellular passage of hydrophilic molecules is limited due to a low rate of transcytotic vesicles, an extremely low pinocytotic activity, expression of active efflux transporters, and high metabolic activity. Paracellular diffusion of hydrophilic molecules and trafficking of immune cells is restricted by a network of tight junctions (TJs)2-5. Due to these characteristics, the BBB is able to protect the CNS from sudden changes in blood composition and uncontrolled influx of immune cells. In a large number of neuro-inflammatory diseases, an impaired function and an opening of the BBB are observed. In diseases of the CNS like multiple sclerosis or stroke or after brain trauma, the BBB becomes inflamed (mediated by for example reactive oxygen species (ROS) and hypoxia) and its function severely impaired which gives rise to enhanced cellular infiltration, thus contributing to tissue damage and neurological deficits. Due to the specialized nature of brain ECs, transmigration of leukocytes through cerebrovascular endothelium is likely to differ from that in other vascular beds. Generally, the transmigration process is closely controlled by the interaction of leukocytes with the endothelial surface followed by low velocity rolling, arrest, firm adhesion, and finally transmigration. For the diapedesis of immune cells across the cerebral vasculature a re-arrangement of the cytoskeleton and opening of the TJ complexes is required to allow cells to pass into the sub endothelial space. In the initial step of the adhesive cascade leukocytes adhere to the endothelium with low affinity. This adhesion is mediated by several members of the selectin family and their corresponding ligands. Despite the low affinity of these interactions, resulting contact of leukocytes with the endothelium leads to further activation of both cell types and finally transmigration of the leukocytes through the BBB6,7. The glycosylation of endothelial cells of different vascular bed origins To date it is unknown which specific carbohydrate structures on the BBB endothelium mediate leukocyte capture and rolling, and whether these structures are differentially expressed onto inflamed brain EC compared to normal brain ECs and vascular beds of other organs. Initial studies using qPCR and FACS analysis within our group reveal that brain endothelial cells have a different profile in their glycosylation-related genes compared to microvascular ECs upon inflammation, which may result in a different glycosylation profile of adhesive structures and may underlie rolling, adhesion and diapedesis of leukocytes. In this project we wish to identify specific, glycosylated structures on brain endothelial cells that mediate capture, rolling and diapedesis of leukocytes in the brain. To investigate the expression of glycosyltransferases in dendritic cells and the changes in expression associated with maturation. RNA preparations from stimulated and non-stimulated hcMEC/D3 (human brain endothelial cells line) and FMVEC (human promary microvascular endothelial cells isolated from foreskins) were sent to both Microarray Core (E) and Core(C). The RNA was put on an RNeasy Column, amplified, labeled, and hybridized to the Glycov3 microarrays. Data was sent to Dr. van Kooyk's lab for analysis.