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The central nervous
system (CNS) is an immune-privileged environment; it is tightly sealed from the
fluctuating milieu of blood by the blood-brain barrier (BBB) formed by brain
endothelial cells (BECs) and the blood-cerebrospinal fluid barrier (BCSFB) composed
by choroid plexus (ChP) epithelial cells (Redzic, 2011). The two main functions of these barriers are to impede free
diffusion between brain fluids and blood and at same time they have to maintain
brain homeostasis by transporting essential nutrients, ions and waste products (Ransohoff et al., 2003;
Takeshita and Ransohoff, 2012).
However, after stroke, brain
tissue inflammation can be detrimental.



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blood-brain barrier (BBB) is formed by microvascular endothelial cells, which
are surrounded by basement membranes, pericytes and astrocytes. Astrocytic endfeet
processes form the glia limitans, which, along with its own basement membrane
and the endothelial basement membrane forms the perivascular space (Man et al., 2007). Moreover,
tight junctions proteins connect the endothelial cells layer and its basement
membrane and constitute the most important seal to prevent diffusion of solutes
(Abbott et al., 2010). Therefore
under normal physiological conditions the vascular system acts as barrier that prevents
the access of molecules and immune cells to the brain, including monocytes and
leukocytes. Different CNS pathologies including secondary inflammation,
compromise BBB integrity and brain vessels become leaky leading fluid
extravasation and brain edema (Choi and Kim, 2008; Stamatovic et al., 2008). After an ischemic stroke
leukocytes are recruited across the vascular endothelial barrier into the
central nervous system (CNS) and it is triggered by several groups of molecules.
P-selectin and P-selectin
glycoprotein ligand 1 (PSGL-1) in leukocytes and vascular cell adhesion
molecule-1 (VCAM-1) and very late antigen-4 (VLA-4) in leukocytes allows the
leukocyte to slow on endothelial cells. Activated leukocyte upregulates the
VLA-4 and lymphocyte function-associated antigen 1 (LFA-1). Binding to VCAM-1
and intercellular adhesion molecule-1 (ICAM-1) on the endothelial cell allows
the activated leukocyte attach to endothelial cells. Leukocytes, then, can
migrate to the brain parenchyma across the endothelial cell via the
paracellular or transcellular pathway (Engelhardt
and Ransohoff, 2005; Engelhardt and Sorokin, 2009; Laschinger and Engelhardt,
2000; Takeshita and Ransohoff, 2012).


Natalizumab, an effective therapy
for multiple sclerosis patients, reduces the invasion of lymphocytes into the
brain 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 antibodies
have been investigated in the stroke field to reduce leukocyte infiltration
into the brain after stroke. Although, inhibition of the cerebral lymphocyte
infiltration showed a reduction of the infarct volume and improved the behavior
outcome after ischemic stroke, being a promising new approach, more research is
needed 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) interconnected
by tight junctions. The ChP is localized in the brain ventricles, filled with
cerebrospinal fluid (CSF). A part from the CSF production, the main function of
the BCSFB is to restrict the entrance of immune cells and molecules into the
brain, as the BBB. Moreover, the ChP is responsible of the brain homeostasis
playing 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 epithelium
surrounding the capillaries and loose connective tissue. ChP epithelium is continuous
with the ventricle ependymal cell layer, but distinct to ependymal, the
epithelial layer has tight junctions that prevent substances to cross the cell
layer into the CSF. Blood vessels inside of the ChP are fenestrated capillaries
and are permeable to molecules and immune cells (Shechter et al., 2013a; Ueno et al., 2016). The ChP stroma is also home to
different immune cells, including macrophages and dendritic cells, serving as a
possible port for these immune cells to enter first to the brain parenchyma (Meeker et al., 2012; Ransohoff and Engelhardt, 2012). After CNS injury, ChP rapidly
responds to pro-inflammatory mediators released from the injured brain
parenchyma or invading inflammatory cells, upregulating the expression of
adhesion 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 epithelial
cells may have an important role in controlling the entrance of these
substances into the brain.


In stroke research,
the endothelial migration across the BBB has been assumed as the main invasion
route for circulating lymphocytes into the ischemic brain (Urra et al., 2014). Although other infiltration routes such as the
ChP have previously been characterized as important entry sites of lymphocytes
in primary inflammatory brain disorders such as experimental autoimmune
encephalitis (EAE) (Ransohoff et al., 2003; Wilson et al., 2010), these alternative
invasion sites have not been analyzed in post-stroke neuroinflammation

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