Abstract
BackgroundIschemic stroke induces the activation and recruitment of peripheral leukocytes to the injured brain. These cells can infiltrate the brain through multiple routes, either by penetrating blood–brain barrier or via blood–CSF barriers at the meninges or the choroid plexus (CP). We previously showed that myeloid cell trafficking via the CP occurs early after neonatal arterial stroke and modulates injury. CD36 is a receptor that mediates function of endothelial cells and cells of the monocyte lineage under various neurodegenerative conditions and can influence brain injury after neonatal stroke. Here we asked whether CD36 impacts injury by altering leukocyte trafficking through the CP in neonatal mice subjected to transient middle cerebral artery occlusion (tMCAO).MethodsIn neonatal mice with intact or globally disrupted CD36 signalling (CD36 KO), we characterized the phenotypes of myeloid cells by flow cytometry and the underlying gene expression signatures in the CPs contralateral and ipsilateral to tMCAO by RNA sequencing analyses, focussing on early post-reperfusion time window.ResultsFlow cytometry in the isolated CPs revealed that CD36 mediates stepwise recruitment of myeloid cells to the CP ipsilateral to tMCAO early after reperfusion, with a predominant increase first in inflammatory monocyte subsets and neutrophils followed by patrolling monocytes. RNA sequencing analyses demonstrated marked changes in gene expression in the CP ipsilateral compared to the CP contralateral to tMCAO in wild type mice. Changes were further modified by lack of CD36, including distinction in several clusters of genes involved in inflammatory, metabolic and extracellular matrix signalling in the CP ipsilateral to tMCAO.ConclusionAltogether, our data suggest cooperation between blood–CSF–brain interface via the CP through CD36-mediated signalling following neonatal stroke with a key role for inflammatory monocytes and neutrophils.
Highlights
Post-stroke inflammation is a double-edged sword in brain injury and involves various cellular players within the brain and infiltrating immune cells [1]
We demonstrate that CD36 mediates recruitment of multiple leukocyte subtypes to the choroid plexus (CP) ipsilateral to transient middle cerebral artery occlusion (tMCAO) early after reperfusion, potentially contributing to increased number of CD45highCD11b+ cells in ischemic-reperfused brain parenchyma. tMCAO triggers marked changes in gene expression in the CP of wild type (WT) pups, including activation of genes involved in inflammatory, metabolic and extracellular matrix signalling, changes that are further modified by lack of CD36
Lack of CD36 alters myeloid cell recruitment to the ipsilateral cortex after tMCAO in neonatal mice First, based on our previous observations that genetic deletion of CD36 leads to much higher incidence of severe injury after acute neonatal stroke, in part due to disrupted immune signaling [21], we sought to determine whether microglial activation and accumulation of myeloid cells in the cortex after tMCAO in neonatal mice is regulated by CD36 signaling
Summary
Post-stroke inflammation is a double-edged sword in brain injury and involves various cellular players within the brain and infiltrating immune cells [1]. Many CD36 ligands are low at birth, likely contributing to the differing CD36 effects between neonatal and adult brain. Ischemic stroke induces the activation and recruitment of peripheral leukocytes to the injured brain. These cells can infiltrate the brain through multiple routes, either by penetrating blood–brain barrier or via blood–CSF barriers at the meninges or the choroid plexus (CP). CD36 is a receptor that mediates function of endothelial cells and cells of the monocyte lineage under various neurodegenerative conditions and can influence brain injury after neonatal stroke. We asked whether CD36 impacts injury by altering leukocyte trafficking through the CP in neonatal mice subjected to transient middle cerebral artery occlusion (tMCAO)
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