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CNS-border associated macrophages respond to acute ischemic stroke attracting granulocytes and promoting vascular leakage.

ABSTRACT: The central nervous system (CNS) contains several types of immune cells located in specific anatomic compartments. Macrophages reside at the CNS borders surrounding the brain vessels, in leptomeningeal spaces and the choroid plexus, where they interact with the vasculature and play immunological surveillance and scavenging functions. We investigated the phenotypic changes and role of these macrophages in response to acute ischemic stroke. Given that CD163 expression is a hallmark of perivascular and meningeal macrophages in the rat and human brain, we isolated CD163⁺ brain macrophages by fluorescence activated cell sorting. We obtained CD163⁺ cells from control rats and 16 h following transient middle cerebral artery occlusion, after verifying that infiltration of CD163⁺ peripheral myeloid cells is negligible at this acute time point. Transcriptome analysis of the sorted CD163⁺ cells identified ischemia-induced upregulation of the hypoxia inducible factor-1 pathway and induction of genes encoding for extracellular matrix components and leukocyte chemoattractants, amongst others. Using a cell depletion strategy, we found that CNS border-associated macrophages participate in granulocyte recruitment, promote the expression of vascular endothelial growth factor (VEGF), increase the permeability of pial and cortical blood vessels, and contribute to neurological dysfunction in the acute phase of ischemia/reperfusion. We detected VEGF expression surrounding blood vessels and in some CD163⁺ perivascular macrophages in the brain tissue of ischemic stroke patients deceased one day after stroke onset. These findings show ischemia-induced reprogramming of the gene expression profile of CD163⁺ macrophages that has a rapid impact on leukocyte chemotaxis and blood-brain barrier integrity, and promotes neurological impairment in the acute phase of stroke.

SUBMITTER: Pedragosa J

PROVIDER: S-EPMC6083589 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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CNS-border associated macrophages respond to acute ischemic stroke attracting granulocytes and promoting vascular leakage.

Pedragosa Jordi J Salas-Perdomo Angélica A Gallizioli Mattia M Cugota Roger R Miró-Mur Francesc F Briansó Ferran F Justicia Carles C Pérez-Asensio Fernando F Marquez-Kisinousky Leonardo L Urra Xabier X Gieryng Anna A Kaminska Bozena B Chamorro Angel A Planas Anna M AM

Acta neuropathologica communications 20180809 1

The central nervous system (CNS) contains several types of immune cells located in specific anatomic compartments. Macrophages reside at the CNS borders surrounding the brain vessels, in leptomeningeal spaces and the choroid plexus, where they interact with the vasculature and play immunological surveillance and scavenging functions. We investigated the phenotypic changes and role of these macrophages in response to acute ischemic stroke. Given that CD163 expression is a hallmark of perivascular ...[more]

PMID: 30092836

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Project description:BackgroundCerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer's disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aβ-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment.MethodsTg2576 mice and WT littermates were transplanted with CD36-/- or CD36+/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36-/- BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined.ResultsThe increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT → Tg2576 chimeras but was fully restored in CD36-/- → Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aβ1-40, but not Aβ1-42, was reduced in CD36-/- → Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36-/- → Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36-/- mice were able to more efficiently clear exogenous Aβ1-40 injected into the neocortex or the striatum.ConclusionsCD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aβ. CD36 deletion in BAM also reduced brain Aβ1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aβ. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate brain BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aβ deposition and damage.

Dataset Information

CNS-border associated macrophages respond to acute ischemic stroke attracting granulocytes and promoting vascular leakage.

Publications

CNS-border associated macrophages respond to acute ischemic stroke attracting granulocytes and promoting vascular leakage.

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