3. Immune cells migrationroutes into the brain after strokeThe central nervoussystem (CNS) is an immune-privileged environment; it is tightly sealed from thefluctuating milieu of blood by the blood-brain barrier (BBB) formed by brainendothelial cells (BECs) and the blood-cerebrospinal fluid barrier (BCSFB) composedby choroid plexus (ChP) epithelial cells (Redzic, 2011). The two main functions of these barriers are to impede freediffusion between brain fluids and blood and at same time they have to maintainbrain homeostasis by transporting essential nutrients, ions and waste products (Ransohoff et al.

, 2003;Takeshita and Ransohoff, 2012).However, after stroke, braintissue inflammation can be detrimental.  Blood-BrainBarrierTheblood-brain barrier (BBB) is formed by microvascular endothelial cells, whichare surrounded by basement membranes, pericytes and astrocytes. Astrocytic endfeetprocesses form the glia limitans, which, along with its own basement membraneand the endothelial basement membrane forms the perivascular space (Man et al.

, 2007). Moreover,tight junctions proteins connect the endothelial cells layer and its basementmembrane and constitute the most important seal to prevent diffusion of solutes(Abbott et al., 2010). Thereforeunder normal physiological conditions the vascular system acts as barrier that preventsthe access of molecules and immune cells to the brain, including monocytes andleukocytes. Different CNS pathologies including secondary inflammation,compromise BBB integrity and brain vessels become leaky leading fluidextravasation and brain edema (Choi and Kim, 2008; Stamatovic et al., 2008).

After an ischemic strokeleukocytes are recruited across the vascular endothelial barrier into thecentral nervous system (CNS) and it is triggered by several groups of molecules.P-selectin and P-selectinglycoprotein ligand 1 (PSGL-1) in leukocytes and vascular cell adhesionmolecule-1 (VCAM-1) and very late antigen-4 (VLA-4) in leukocytes allows theleukocyte to slow on endothelial cells. Activated leukocyte upregulates theVLA-4 and lymphocyte function-associated antigen 1 (LFA-1). Binding to VCAM-1and intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell allowsthe activated leukocyte attach to endothelial cells. Leukocytes, then, canmigrate to the brain parenchyma across the endothelial cell via theparacellular or transcellular pathway (Engelhardtand Ransohoff, 2005; Engelhardt and Sorokin, 2009; Laschinger and Engelhardt,2000; Takeshita and Ransohoff, 2012). Natalizumab, an effective therapyfor multiple sclerosis patients, reduces the invasion of lymphocytes into thebrain by blocking ? chain of VLA-4 (anti-CD49d antibodies)(Polman et al., 2006; Rice et al., 2005; Steinman,2005; Yednock et al.

, 1992). Therefore, anti-CD49 antibodieshave been investigated in the stroke field to reduce leukocyte infiltrationinto the brain after stroke. Although, inhibition of the cerebral lymphocyteinfiltration showed a reduction of the infarct volume and improved the behavioroutcome after ischemic stroke, being a promising new approach, more research isneeded before translating these findings into clinic (Liesz et al., 2009; Liesz et al., 2011). Blood-cerebrospinal fluid barrier The blood-cerebrospinal fluid barrier(BCSFB) is formed by the epithelial cells of the choroid plexus (ChP) interconnectedby tight junctions. The ChP is localized in the brain ventricles, filled withcerebrospinal fluid (CSF). A part from the CSF production, the main function ofthe BCSFB is to restrict the entrance of immune cells and molecules into thebrain, as the BBB.

Moreover, the ChP is responsible of the brain homeostasisplaying an important role as filtration system, removing metabolic waste (Mortazavi et al., 2014; Ransohoff et al., 2003;Wilson et al., 2010).The ChP is formed by a cuboidal epitheliumsurrounding the capillaries and loose connective tissue.

ChP epithelium is continuouswith the ventricle ependymal cell layer, but distinct to ependymal, theepithelial layer has tight junctions that prevent substances to cross the celllayer into the CSF. Blood vessels inside of the ChP are fenestrated capillariesand are permeable to molecules and immune cells (Shechter et al., 2013a; Ueno et al., 2016). The ChP stroma is also home todifferent immune cells, including macrophages and dendritic cells, serving as apossible port for these immune cells to enter first to the brain parenchyma (Meeker et al., 2012; Ransohoff and Engelhardt, 2012).

After CNS injury, ChP rapidlyresponds to pro-inflammatory mediators released from the injured brainparenchyma or invading inflammatory cells, upregulating the expression ofadhesion molecules and chemokines that are essential for lymphocyte trafficking(Ghersi-Egea et al., 2018; Shechter et al., 2013b;Szmydynger-Chodobska et al., 2012) (Fig.1).

Therefore, ChP epithelialcells have an important role in controlling the entrance of these substancesinto the brain. Instroke research, the endothelial migration across the BBB has been assumed asthe main invasion route for circulating lymphocytes into the ischemic brain (Urra et al., 2014). Although otherinfiltration routes such as the ChP have previously been characterized asimportant entry sites of lymphocytes in primary inflammatory brain disorderssuch as experimental autoimmune encephalitis (EAE) (Ransohoff et al., 2003; Wilson et al., 2010), these alternative invasion siteshave not been analyzed in post-stroke neuroinflammation.

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