Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke

BBADIS-64346; No. of pages: 11; 4C: 5, 6, 7 Biochimica et Biophysica Acta xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis

Review

Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke☆ Melissa A. Lopes Pinheiro a, Gijs Kooij a, Mark R. Mizee a, Alwin Kamermans a, Gaby Enzmann b, Ruth Lyck b, Markus Schwaninger c, Britta Engelhardt b, Helga E. de Vries a,⁎ a b c

Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands University of Bern, Theodor Kocher Institut, Freiestrasse 1, 3012 Bern, Switzerland Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Ratzeburger Allee 160, 23562 Lübeck, Germany

a r t i c l e

i n f o

Article history: Received 8 September 2015 Received in revised form 17 October 2015 Accepted 20 October 2015 Available online xxxx Keywords: Blood–brain barrier Immune cell trafficking Multiple sclerosis Stroke Astrocyte

a b s t r a c t Each year about 650,000 Europeans die from stroke and a similar number lives with the sequelae of multiple sclerosis (MS). Stroke and MS differ in their etiology. Although cause and likewise clinical presentation set the two diseases apart, they share common downstream mechanisms that lead to damage and recovery. Demyelination and axonal injury are characteristics of MS but are also observed in stroke. Conversely, hallmarks of stroke, such as vascular impairment and neurodegeneration, are found in MS. However, the most conspicuous common feature is the marked neuroinflammatory response, marked by glia cell activation and immune cell influx. In MS and stroke the blood–brain barrier is disrupted allowing bone marrow-derived macrophages to invade the brain in support of the resident microglia. In addition, there is a massive invasion of auto-reactive T-cells into the brain of patients with MS. Though less pronounced a similar phenomenon is also found in ischemic lesions. Not surprisingly, the two diseases also resemble each other at the level of gene expression and the biosynthesis of other proinflammatory mediators. While MS has traditionally been considered to be an autoimmune neuroinflammatory disorder, the role of inflammation for cerebral ischemia has only been recognized later. In the case of MS the long track record as neuroinflammatory disease has paid off with respect to treatment options. There are now about a dozen of approved drugs for the treatment of MS that specifically target neuroinflammation by modulating the immune system. Interestingly, experimental work demonstrated that drugs that are in routine use to mitigate neuroinflammation in MS may also work in stroke models. Examples include Fingolimod, glatiramer acetate, and antibodies blocking the leukocyte integrin VLA-4. Moreover, therapeutic strategies that were discovered in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, turned out to be also effective in experimental stroke models. This suggests that previous achievements in MS research may be relevant for stroke. Interestingly, the converse is equally true. Concepts on the neurovascular unit that were developed in a stroke context turned out to be applicable to neuroinflammatory research in MS. Examples include work on the important role of the vascular basement membrane and the BBB for the invasion of immune cells into the brain. Furthermore, tissue plasminogen activator (tPA), the only established drug treatment in acute stroke, modulates the pathogenesis of MS. Endogenous tPA is released from endothelium and astroglia and acts on the BBB, microglia and other neuroinflammatory cells. Thus, the vascular perspective of stroke research provides important input into the mechanisms on how endothelial cells and the BBB regulate inflammation in MS, particularly the invasion of immune cells into the CNS. In the current review we will first discuss pathogenesis of both diseases and current treatment regimens and will provide a detailed overview on pathways of immune cell migration across the barriers of the CNS and the role of activated astrocytes in this process. This article is part of a Special Issue entitled: Neuro inflammation: A common denominator for stroke, multiple sclerosis and Alzheimer's disease, guest edited by Helga de Vries and Markus Swaninger. © 2015 Elsevier B.V. All rights reserved.

1. Multiple sclerosis ☆ This article is part of a Special Issue entitled: Neuro inflammation: A common denominator for stroke, multiple sclerosis and Alzheimer's disease, guest edited by Helga de Vries and Markus Swaninger. ⁎ Corresponding author at: Department of Molecular Cell Biology and Immunology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: [email protected] (H.E. de Vries).

The first description of a patient with multiple sclerosis (MS) was possibly the case of Lidwina (1380–1433) from Schiedam (The Netherlands). Her disease began at the age of 16, soon after a fall while ice skating [1,2]. At the age of 19, both her legs were paralyzed

http://dx.doi.org/10.1016/j.bbadis.2015.10.018 0925-4439/© 2015 Elsevier B.V. All rights reserved.

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

2

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

and vision problems started. She developed symptoms consistent with MS, as we currently know it, as well as the age of onset and disease course, suggesting that the first MS diagnosis dates back to the 14th century. During the 19th century, other descriptions of patients with similar symptoms emerged. Jean-Martin Charcot, the “father of neurology”, was an important figure in MS research, since he was the first to make the story of MS coherent. He examined the brain of a MS patient and found scars or “plaques” characteristic of MS. In 1868, he wrote “La sclerose en plaques” providing a full description of the disease and accompanying changes in the brain [1,2]. He was also the first to develop diagnostic criteria, known as the Charcot triad [1]. MS is seen as a heterogeneous disease since lesions are multifocal and the neurological signs are highly dependent on their location and extension resulting in a wide variety of clinical symptoms. MS lesions are usually located in the white matter around the ventricles, optic nerve, corpus callosum, cerebellum, spinal cord, brain stem or in subcortical gray matter regions [1]. Symptoms can include visual disturbance, muscle weakness, difficulties in coordination and balance, numbness or tingling, memory problems, or changes in bowel and bladder function. Less diagnostic but equally debilitating symptoms include cognitive changes, fatigue and mood alterations [3–5]. MS can be subdivided in several clinical forms: relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and progressive relapsing MS (PRMS). The great majority of MS patients (approximately 85%) have RRMS which is characterized by acute attacks (relapses) which can last from a few days to weeks, followed by a period of partial or full recovery (remission) of the symptoms [1]. Usually patients with RRMS have no worsening of neurological function between relapses. SPMS is characterized by initial relapses followed by a more progressive phase with gradual deterioration of neurological function not associated with acute attacks. Patients might present occasional relapses or minor remissions [1]. Approximately 50% of RRMS patients convert to SPMS after 10 years and 90% after 25 years. Between 10-15% of MS patients develop PPMS, which is characterized by the lack of relapses, with increased functional decline from the onset of the disease. Patients occasionally show plateaus or temporary minor improvements. Like PPMS, PRMS is characterized by steady functional decline since onset, but in later stages patients present acute attacks, hence these two forms cannot be distinguished in early stages of the disease [1,3]. As the disease progresses severe disability may occur, with a median time of 10 years to reach walking impairment [3]. Due to its heterogeneous nature, there is no single test or specific clinical feature diagnostic for MS. However, analysis of the cerebralspinal fluid (CSF) may support the clinical diagnosis since more than 90% of MS patients shows increased immunoglobulin load and two or more oligoclonal bands in the CSF. A way to detect and demonstrate MS lesions is by using magnetic resonance imaging (MRI). It is usually used to support the diagnosis, estimate lesion load and their location, disease activity, atrophy level of the brain and axonal loss [1]. MS is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) characterized by the presence of lesions or plaques in the brain [6]. These demyelinating lesions are composed of perivascular infiltrates of namely CD4+ and CD8+ T cells, monocytederived macrophages and occasionally plasma cells [7]. In these socalled active lesions, immune cells further traffic to the brain parenchyma initiating an autoimmune response against myelin antigens leading to cell and tissue damage. As the disease progresses to the chronic phase, gradual lesion expansion is observed, together with myelinladen macrophages present in the lesion edge, demyelinated axons and neurodegeneration, oligodendrocyte injury or death, microglia activation and astrogliosis [8–10]. Due to the importance of the immune system in disease progression, MS was for a long time considered an autoimmune disease. Much of what we know so far results from experiments in the animal model for MS — Experimental Autoimmune Encephalomyelitis

(EAE). The acute mouse model of EAE is induced in susceptible mouse strains by active immunization of the animals with CNS homogenates, myelin or myelin-derived antigens such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) or myelin proteolipid protein (PLP) emulsified in adjuvant [11]. Upon immunization, antigen presenting cells mature in the lymph nodes where they present myelin-derived peptides to naïve T cells [12]. During this process, upregulation of co-stimulatory molecules such as CD80, CD86 and CD40 which interact with CD28 and CD40 ligand, as well as secretion of pro-inflammatory cytokines mediate the activation and differentiation of T cells. In mice, differentiation of CD4+ T helper cells into proinflammatory interferon-gamma (IFN-γ) or interleukin-17 (IL-17)-producing Th1 and Th17 cells, respectively, has been shown essential for EAE induction [13]. Therefore, active EAE is a T cell-driven autoimmune disease where pathogenic auto-reactive Th1 and Th17 cells mediate the disease process [13]. Furthermore, differentiation of naïve T cells into T cells with a suppressive function (regulatory T cells — Tregs) is also present in EAE and has been shown important for disease recovery [12]. Importantly, this model allows the study of T cell mediated processes of disease. In humans, the role of specific T helper subtypes is not as clear as it is in EAE. It has been shown in the early 90s that, instead of being completely deleted by negative selection in the thymus, myelin-reactive CD4+ T cells are present in the peripheral blood of MS patients as well as healthy individuals [14]. However, a recent study has shown that myelin-reactive T cells from MS patients produced high levels of IFN-γ, IL-17 and granulocyte-macrophage colonystimulating factor (GM-CSF), compared to healthy controls, which mainly produced IL-10 [15]. Although the frequency of myelin-specific T cells is unchanged between MS patients and controls, it has been shown that Treg cells from RRMS patients had a decreased suppressor function when compared to Treg cells from healthy controls or SPMS patients [16,17]. On the other hand, it has been suggested that effector T cells from RRMS patients are actually resistant to suppression by Treg cells [18]. These results suggest that the mechanism for tolerance failure in MS is complex but might have an important contribution in MS pathogenesis. Although MS was for a long time considered an autoimmune disease, it is nowadays clear that the pathogenesis of MS is more intricate than initially thought, with progressive neurodegeneration in addition to inflammatory processes [1]. The autoimmune model of MS has been challenged by the “inside-out” hypothesis of MS etiology, where it is argued that an initial degenerative event begins in the CNS, with an autoimmune response as a secondary event [19]. Some reports have provided evidence for this model. One study has described early MS lesions with few or any infiltrated lymphocytes, but with oligodendrocyte loss and microglia activation in a RRMS patient that had died right after a relapse. This intriguing report suggests that oligodendrocyte death could be the trigger of the adaptive immune response and underlies the possibility of other processes contributing for lesion formation in MS [20,21]. Other studies have observed myelin damage beyond areas of inflammation, suggesting that myelin injury could precede inflammatory events [22]. Importantly, it is known that antiinflammatory drugs used by RRMS patients have no effect in PPMS [23,24] suggesting that a degenerative mechanism could be the primary initiating event. Most of the currently used disease-modifying treatments (DMTs) immunosuppressive or immunomodulatory [25] and include interferonbeta (IFN-β) (Avonex, Rebif, Betaseron and Extavia), glatiramer acetate (Copaxone), Natalizumab (Tysabri) [3] and the new oral drugs fingolimod (Gilenya), teriflunomide (Aubagio) and dimethyl fumarate (Tecfidera) [26] [3,27–30]. IFNβ and glatiramer acetate are usually used as a first line treatment [31]. If patients do not respond to these DMTs, other treatment options are considered. Natalizumab is a monoclonal antibody which prevents the entry of immune cells into the brain by blocking the interaction of the integrin very late antigen-4 (VLA-4) on immune cells with vascular cell adhesion molecule-1 (VCAM-1) present on the

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

inflamed brain endothelium. Because IFNβ and glatiramer acetate are administered subcutaneously or intramuscularly, it might affect patient acceptance and adherence to the treatments [31]. Therefore, oral DMTs for MS have the advantage of easier administration. Fingolimod functionally antagonizes sphingosine-1-phosphate receptors on T lymphocytes blocking their egress from secondary lymphoid organs [32,33]. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway helping in the production of endogenous cytoprotective antioxidants, which was proposed to have both an anti-inflammatory and a neuroprotective action [34]. Teriflunomide was shown to inhibit the proliferation of activated T and B cells leaving the homeostatic proliferation (self-renewal) of resting cells unchanged [35]. Although much effort has been made to develop safe and effective drugs for MS, a big challenge remains for the treatment of MS patients with a more progressive disease, where effective DMTs are still inexistent. 2. Cerebral ischemia Of the one million patients afflicted with stroke each year in the European Union 80% will suffer an ischemic stroke. There, blood supply to a certain area of the brain is obstructed by either formation of a local thrombus or the migration of a peripherally formed clot into the brain until lodging into a blood vessel too narrow to pass. This results in the formation of an ischemic core with no surviving cells surrounded by a salvageable penumbra given immediate medical intervention, e.g. thrombolysis (for review see [36]). The middle cerebral artery (MCA) irrigating most of the cortex, the basal ganglia and the internal capsule is the most common site for ischemic stroke. Depending on the occluded area, functional deficits therefore vary greatly. More recently delayed exofocal postischemic neuronal damage has been reported and proposed as a target for future neuroprotective therapies [37]. The remaining 20% of stroke cases constitute of haemorrhagic stroke are caused by the rupture of weakened blood vessels intracerebrally or in the subarachnoidal compartment. Blood vessels prone to rupture are mainly aneurysms or arteriovenous malformations. In haemorrhagic stroke blood constituents released uncontrollably from the circulation can both irritate and compress the surrounding tissue. Cerebral ischemia in humans is divided in three stages. Within hours after stroke neuronal microvacuoles can be detected, the cytoplasm becomes eosinophilic, pyknotic nuclei appear and the blood–brain barrier (BBB) is compromised. Additionally, leukocytes start to infiltrate the damaged area at stage I. At stage II, which can last for weeks macrophages appear and astrocytes proliferate. During the chronic phase at stage III a pseudocyst is forming [38]. It is therefore clear that stroke, which has an acute onset differs from multiple sclerosis (MS) which progresses more chronically. Time is of essence to contain damage to the CNS in the event of an embolic stroke. Reperfusion (RP) provided by means of thrombolytic intervention allows for limited salvation of neurons in the penumbra as opposed to cells in the core of the lesion [36]. However, transient experimental ischemia followed by RP results in exacerbation of lesion pathology when compared to animals subjected to permanent ischemia [39]. There is general agreement that the immune system plays an important role in the outcome of ischemic stroke. However present findings in animal models of stroke do not yet allow coming to a final conclusion about the specific role of the individual immune cell subsets in the outcome of stoke. Polymorphonuclear granulocytes (PMNs) are the first subset of leukocytes to appear in the ischemic brain and were therefore suspected to convey further harm to pre-damaged neurons (for critical review see Ref. [40]). It has long been thought that after ischemic stroke PMNs extravasate into the brain parenchyma and cause further neuronal cell death. However, more recently it has been found that during the acute phase of RP neutrophils are not found in the brain parenchyma but

3

rather remain trapped within the confines of the neurovascular unit and the leptomeningeal spaces [41,42]. Considering the early time points when neuronal cell death is observed after ischemic stroke, absence of neutrophils in transient ischemia cannot be reconciled with the assumption that neutrophil-mediated neuronal cell death requires their physical presence adjacent to the target. Employing a panel of antibodies recognizing various laminin isoforms defining the distinct constituents of the endothelial and parenchymal basement membrane of blood–brain barrier (BBB) allowed to define the presence of PMNs in the leptomeningeal compartment, the luminal aspect of cerebral microvessels and the perivascular space. Detection of PMNs in the CNS parenchyma mainly coincided with gross destruction of adjacent blood vessels. Lack of active multi-step migration of PMNs across the BBB during early RP was not an observation limited to the choice of animal models but could also be observed in human stroke specimen [42]. Finally, investigating PMN extravasation across the BBB in vitro under physiological flow confirmed that ischemia does not suffice to trigger PMN migration into the brain [42]. As soon as PMNs decline in number Ly6Chigh inflammatory monocytes are recruited in a CCR2-dependent manner, populate the ischemic area and differentiate into noninflammatory Ly6Clow/F4/80high mature phagocytes. Depletion of either blood derived monocytes by chlodronate-filled liposomes or ablation of myeloid cells in the hematogenous compartment by employing either CD11b-DTR or bone marrow chimeric mice worsens the clinical outcome after stroke demonstrating a beneficial effect of these cells for stroke outcome. The importance of early monocyte recruitment for delayed repair processes and stabilization of the neurovascular unit is further underscored by the observation of an increased incidence of secondary hemorrhagic transformation of newly formed blood vessels in the penumbra of these mice [43]. In apparent contrast to these findings it was observed that CCR2-deficient mice are protected against ischemia and RP injury due to leukocyte infiltration into the CNS and reduced expression of inflammatory cytokines in the CNS [44]. An earlier study furthermore demonstrated that fractalkine (CX3CL1) deficiency ameliorates cerebral ischemia [45]. Ablation of post-ischemic proliferating resident microglia employing CD11b-thymidine kinase mutant-30 mice proofed detrimental in stroke pathology pointing to a role of microglia in modulating brain inflammation. Most importantly, proliferating microglia serves as a source of endogenous neurotrophic molecules such as IGF-1 containing further tissue damage [46]. There are also conflicting findings regarding the role of Treg cells in cerebral ischemia. Depletion of Forkhead box P3 (FoxP3) Treg cells in the DEREG mouse model appeared beneficial and reduced the lesion size and improved the functional outcome for an extended period after stroke. Treg cells were assumed to induce microvascular dysfunction by increased Treg- endothelial interaction via the integrin leukocyte function-associated antigen (LFA)-1 on lymphocytes and the endothelial Intercellular adhesion molecule (ICAM)-1 on inflamed microvessels. Binding of Treg cells to platelets via CD40-CD40 ligand could further impair tissue reperfusion and cause neuronal cell death. In conclusion, Treg cells appear detrimental in the delayed phase of stroke [47]. Another study employing Treg depleted mice by means of an anti-CD25 antibody reported cerebroprotective effects of Treg cells in an ischemic setting [48]. There, absence of Treg cells resulted in increased lesion size and worsening of the functional outcome. Depletion of Treg was accompanied by upregulation of certain pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF)-α and IFN-γ and T lymphocytes and microglia were revealed as major cytokine source. Interleukin (IL)-10 was identified as the main regulator of the cerebroprotective effect of Treg cells. As a consequence of cerebral ischemia there is a higher incidence for stroke patients to develop delayed cognitive deficits. Oligoclonal bands were detected in the CSF of some patients indicating a contribution of B-lymphocytes to dementia. In animal models activated B-lymphocytes and secreted antibodies were detected in the lesioned

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

4

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

parenchyma at later time points after stroke. There, genetic or pharmacological ablation of B-lymphocytes, μMT mice and anti-CD20 antibody, respectively, proofed to be beneficial in preventing cognitive decline [49]. In contrast, cerebral ischemia in B-cell-deficient μMT mice resulted in higher mortality, severe functional deficits and aggravated contribution of inflammatory cells compared to wildtype control animals. Application of IL-10 secreting B-lymphocytes to μMT mice was able to reverse these effects. These results point to a regulatory function of B-lymphocytes in ameliorating deficits following cerebral ischemia [50]. In accordance to the confusing findings about the contribution of different immune cell subsets to the outcome of ischemic stroke studies aiming to interfere with leukocyte trafficking into the CNS for the treatment of stroke have also produced apparently discrepant findings. Based on the general agreement on the devastating effect of neutrophils to the outcome of ischemic stroke, first efforts to treat stroke were aimed at inhibiting neutrophil migration into the brain after ischemic stroke. Indeed experimental stroke models aimed at blocking neutrophil - endothelial interaction showed amelioration of disease progression and thus raised hopes for clinical translation allowing improving the situation for stroke patients. ICAM-1-deficient C57BL/6 mice (Icam1tm1Jcgr) were shown to display improved cerebral blood flow and functional outcome as well as a reduction of the infarct volume compared to wild-type C57BL/6 mice when subjected to tMCAO [51]. Combined with the observation that neutrophil depletion ameliorated stroke these studies suggested an important role for ICAM-1-mediated neutrophil adhesion to cerebral vessels in the pathophysiology of an evolving stroke. Translation of this therapeutic approach into the clinic has however severely failed. In the Enlimomab phase III clinical trial a monoclonal murine anti-human ICAM-1 antibody (R6.5) designed to inhibit ICAM-1 mediated neutrophil adhesion to cerebral microvessels during the acute phase of stroke caused neurological deficits and even increased mortality [52]. In retrospect, sensitization against murine epitopes and in vivo activation of neutrophils by the antibody was hold accountable for the adverse effects [53,54]. On the other hand the ICAM-1 mutants employed in the pre-clinical stroke studies, which were created by either disrupting exon 4 (Icam1tm1Jcgr) [55] or exon 5 (Icam1tm1Bay) [56] of the ICAM-1 gene, have been shown to still express functional splice variants of ICAM-1 [57] that affect leukocyte adhesion and migration [58] and the outcome of autoimmune neuroinflammation [59]. More recently it has been suggested that VLA-4 is expressed on neutrophils. Pharmacological blockade of VLA-4 (CD49d/CD29) proofed efficacious in some studies [60,61] and reduced infiltration by T lymphocytes and neutrophils, respectively. There, interference with the VLA-4/VCAM-1 axis resulted in improved functional outcome after stroke. Another study failed however to detect any improvement despite measurable blockade of the egress of leukocytes [62]. Considering these discrepant observations and resulting failure to translate any of these findings into the clinic a recent preclinical randomized controlled multicenter trial was launched to study anti-CD49d treatment for acute brain ischemia. These results pooled from all participating research centers demonstrated that blocking CD49d reduced leukocyte infiltration into the brain and infarct volume in a model causing small cortical infarcts but not in a model inducing large lesions [63]. These observations suggest that the success of therapeutic targeting of immune cell migration into the CNS after ischemic stroke might critically depend on infarct severity and localization. Taken together, after ischemic stroke is accompanied by the accumulation of different immune cell subsets in the brain as observed in MS therapeutic targeting of immune cell trafficking to the CNS for the treatment of stoke awaits further studies. 3. Immune cell trafficking into the brain For a long time, it was believed that no immune surveillance occurred in the CNS [64]. This traditional view of lack of immune cell

infiltration in the healthy brain came from experiments where it was observed that allo- or xenogeneic tissue grafts implanted in the brain were less easily rejected by the recipient when compared to transplantation to the orthotopical sites [65]. Furthermore, because the CNS is devoid of a conventional lymphatic system and the CNS parenchyma is devoid of cells constitutively expressing MHC class I and class II, the idea emerged that in the brain antigens could not be recognized by CD4+ T cells [66]. In the meanwhile it is well accepted that the CSF drained spaces of the CNS, i.e. the perivascular, leptomeningeal and ventricular spaces can be accessed by activated cells of the adaptive immune system in the absence of neuroinflammation in their search for their cognate antigen. In these spaces bone marrow derived macrophages and dendritic cells (DCs) present CNS antigens [67]. Also antigens in the CSF drain from the leptomeningeal spaces across the cribriform plate of the ethmoid bone towards the nasal submucosa to cervical lymph nodes making antigens of the CSF space visible to the peripheral immune system [68].

3.1. Role of the choroid plexus Data is accumulating that CNS specific immune processes like immune surveillance are regulated by a unique neuro-immunological interface, called the choroid plexus (CP) [69]. This highly vascularized brain structure resides in the brain ventricles and consists of an epithelial layer forming the tight blood-cerebrospinal fluid barrier (BCSFB), which surrounds a core of fenestrated capillaries and connective tissue. The CP is originally known as the main producer of CSF, which fills all brain ventricles, subarachnoid spaces and perivascular spaces and thereby reaches a large surface area of the CNS. The finding that the level of pro-inflammatory immune cell presence (T cells, B cells and macrophages) in the CSF of MS patients correlates with the number of CNS lesions [70] illustrates that immune cell trafficking may occur across the BCSFB (Fig. 1). At the CP, the epithelial cells form a tight barrier may express high levels of adhesion molecules and chemokines that are required for leukocyte trafficking [71]. Before blood-derived leukocytes enter the CSF, they first pass fenestrated capillaries and accumulate in the CP parenchyma in which the antigen presenting cells, DCs, are located [72]. By virtue of antigen presentation, DCs can skew immune cells towards an inflammatory or anti-inflammatory phenotype depending on their inflammatory or tolerogenic phenotype [73]. It is plausible to hypothesize that due to this unique localization between the CNS and the periphery, these DCs present CNS antigens and can therefore be regarded as crucial regulatory players of CNS immune processes. Indeed, using high-throughput analysis of the T cell receptor repertoire in the CP, it was recently shown that the majority of T cells in the CP stroma are specific for CNS antigens [74]. To enter the CSF, immune cells have to pass the CP epithelial cells which express various adhesion molecules, cytokines and chemokines that can mediate leukocyte trafficking [75]. These epithelial cells are interconnected by tight junctions (TJs), and in particular CLDN3 [76]. Importantly, we have shown previously that the expression of this CP-specific TJ molecule was severely reduced in MS. Consequently, mice that lack CLDN3 display exacerbated clinical signs of EAE, which coincided with enhanced levels of infiltrated leukocytes in their CSF [76]. These findings strengthen the role of the CP in MS pathogenesis, indicating that CP integrity may be regarded as a crucial determinant of leukocyte-CSF entry. After passing the BCSFB, CSF-infiltrated leukocytes produce large amounts of inflammatory mediators like proinflammatory cytokines which are thought to activate endothelial cells of the brain vasculature, by inducing the expression of adhesion molecules and chemokines. In turn, this facilitates a massive ‘second wave’ of immune cell entry into the brain parenchyma through the BBB, leading to the formation of inflammatory lesions [77,78]. In contrast to the epithelial cells of the CP, the migration process of leukocytes across the endothelial cells of the BBB is much better understood.

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

5

Fig. 1. Choroid plexus in health and disease. In the choroid plexus, fenestrated blood vessels lie within the choroid plexus parenchyma. These vessels are surrounded by choroid plexus epithelial cells establishing the blood–CSF-barrier. Leukocytes can easily pass the fenestrated blood vessels and enter the choroid plexus parenchyma but rarely enter the CSF due to (tight) barrier properties of the epithelial cells. During neuro-inflammation, however, these barrier properties are altered and chemokine production is highly increased, thereby facilitating the entry of immune cells in the CSF. Here, T cells engage their cognate peptide–major histocompatibility complex expressed on resident dendritic cells, which in turn triggers the release of inflammatory cytokines into the CSF. Subsequently, blood vessels in the brain become inflamed inducing a ‘second wave’ of immune cell migration across the BBB.

In the choroid plexus, fenestrated blood vessels lie within the choroid plexus parenchyma. These vessels are surrounded by choroid plexus epithelial cells establishing the blood-CSF-barrier. Leukocytes can easily pass the fenestrated blood vessels and enter the choroid plexus parenchyma but rarely enter the CSF due to (tight) barrier properties of the epithelial cells. Here, T cells engage their cognate peptide-major histocompatibility complex expressed on resident DCs, which in turn triggers the release of inflammatory cytokines into the CSF. During neuro-inflammation, barrier properties of the BCSFB are altered and chemokine production is highly increased, thereby facilitating the entry of immune cells in the CSF. A direct role for the chemokine CCL20 constitutively expressed in choroid plexus epithelial cells could be shown in directing CCD6+ Th17 cells across the BCSFB during the initiation of EAE [78]. Adhesion molecules such as ICAM-1 and VCAM-1 are however displayed on the luminal side of the choroid plexus epithelium [79,80] and their role in immune cell trafficking across the BCSFB remains to be shown. The major challenge in the coming years is to understand how the CP regulates immune cell trafficking under healthy and pathological conditions, to ultimately provide new ways to control CSF-entry and hamper neuro-inflammation.

3.2. Lymphocyte diapedesis across the blood–brain barrier Lymphocyte migration into the CNS parenchyma is one of the hallmarks in MS lesion formation. It is a multi-step process taking place at the level of post-capillary venules that requires close contact between lymphocytes and the brain endothelium (Fig. 2). The first phase of the multi-step leukocyte extravasation involves overcoming the shear forces mediated by blood flow and requires the interaction of circulating lymphocytes with the endothelium through cell–cell interactions mediated by cell surface molecules. Therefore, the first point of contact is transient and occurs when selectin-ligands on the lymphocyte surface, such as PSGL-1 [81,82] interact with E- and P-selectin in inflamed meningeal vessels [83,84]. These interactions allow the cells to tether and slowly roll along the vascular wall. The lymphocytes can then bind chemokines presented on the endothelial luminal surface. During neuro-inflammation, endothelial cells upregulate expression of chemoattractants such as chemokines [85]. It has been described that CCL19 is expressed at the BBB and upregulated in MS and it is thought to mediate the activation of CCR7+ T cells [86].

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

6

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

Fig. 2. Multi-step process of lymphocyte diapedesis through the BBB. Lymphocyte transendothelial migration has been described as a sequential set of events involving adhesion and rolling, activation of chemokine receptors on the immune cells through contact with chemokines present in the endothelial surface, firm arrest and subsequent crawling of the lymphocyte to determine a permissive site for diapedesis. After overcoming the shear forces induced by blood flow, lymphocytes first contact the endothelium via PSGL-1 which interacts with E- and P-selectin in inflamed endothelial cells. The lymphocytes then bind chemokines presented on the endothelial luminal surface such as CCL19. The binding of chemokines to G-proteincoupled receptors (GPCRs) in the lymphocyte surface delivers an inside-out signal to integrins such as VLA-4 and LFA-1 leading to their conformational change and increased avidity for the endothelial adhesion molecules ICAM-1 and VCAM-1 mediating the arrest of the lymphocytes on the BBB. Once the lymphocyte has arrested, it may then polarize and begin to crawl. Binding to ICAM-1 triggers an intracellular signaling cascade in the endothelium and docking structure formation (inset), preparing the cell for the last step of the process — the diapedesis. Lymphocyte diapedesis can occur in two different ways: the paracellular route involves migration across adjacent endothelial cells whereas in the transcellular route the lymphocyte migrates through a single endothelial cell, where the formation of a channel or pore is required.

CCL2 has been shown to be released by cultured endothelial cells and upregulated in MS lesions, most likely having an effect on lymphocyte and monocyte migration through the BBB [87–89]. Brain endothelial cells also express high levels of CXCL10 and CXCL8 in vitro [87] which may contribute to the pro-inflammatory response observed in MS. The binding of chemokines to G-protein-coupled receptors (GPCRs) in the lymphocyte surface delivers an inside-out signal to α4β1 (VLA-4) and αLβ2 (LFA-1) integrins leading to their conformational change and clustering. This altered form increases the affinity and avidity to the endothelial ligands ICAM-1 and VCAM-1 therefore mediating the arrest of the lymphocytes on the BBB [90–93]. Once the lymphocyte has arrested, it may then polarize and begin to crawl. Crawling of effector CD4+ T lymphocytes predominantly against the direction of flow as demonstrated during the onset of EAE in superficial spinal cord vessels in vivo [94] or on cytokine stimulated BBB endothelium in vitro [95]. This directional crawling against flow relies on a concerted turnover of LFA-1 [96,97] interacting with endothelial ICAM-1 or in addition with endothelial ICAM-2 [95,98]. The distance of crawling prior to diapedesis is determined by the level of endothelial ICAM-1 with high ICAM-1 cell surface levels leading to shorter crawling distances prior to diapedesis [99]. During crawling lymphocytes probe the endothelial surface for a site permissive for diapedesis [95,100, 101]. Importantly, binding to ICAM-1 triggers an intracellular signaling cascade in the endothelium and docking structure formation, preparing the cell for the last step of the process — the diapedesis. Lymphocyte diapedesis can occur in two different ways: the paracellular route involves migration across adjacent endothelial cells and requires transient

junctional rearrangement; whereas in the transcellular route the lymphocyte migrates through a single endothelial cell, where the formation of a channel or pore is required [102]. In this context endothelial ICAM-1 takes a central role with low endothelial cell surface levels of ICAM-1 directing T cells preferentially to paracellular sites of diapedesis while high cell surface levels of endothelial ICAM-1 enhance transcellular diapedesis of T cells across the BBB [99]. Importantly, the cellular pathway of T cell diapedesis is regulated by mechanisms distinct from those regulating barrier integrity of the BBB during neuroinflammation [99]. ICAM-1 is probably the most prominent upstream adhesion molecule responsible for transducing outside-in signals to brain endothelial cells. Several studies have demonstrated the crucial role of ICAM-1 and its downstream signaling during leukocyte migration. Importantly, the firm adhesion of leukocytes to the brain endothelium induces the clustering of ICAM-1, which in turn triggers the activation of intracellular signaling pathways involved in actin cytoskeleton and junctional remodeling necessary for transendothelial migration to occur [85]. It has been shown that cross-linking of ICAM-1 in brain endothelial cells results in the activation of the tyrosine kinase p60src and consequent phosphorylation and activation of the actin-binding protein, cortactin [103]. Interestingly, p60src activation was shown to be dependent on intracellular calcium and protein kinase C (PKC) activity [104]. Furthermore, tyrosine phosphorylation of focal adhesion kinase (FAK), p139cas and paxillin, which are also involved in cytoskeleton rearrangements, was shown to be dependent on the activity of PKC and the small Rho guanosine triphosphatase (GTPase) [104,105]. An important mediator of ICAM-1 signaling is its C-terminal intracellular domain. It has

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

been demonstrated that brain endothelial cells devoid from this cytoplasmic tail are unable to activate Rho GTPase and therefore transendothelial migration is impaired in these cells but with no effect on adhesion [106,107]. Lastly, ICAM-1 cross-linking has also been implicated in junctional remodeling. It has been described that VE-cadherin tyrosine phosphorylation is enhanced after ICAM-1 clustering resulting in junction disengagement, a process essential during paracellular migration [108]. Additionally, ICAM-1-induced VE-cadherin phosphorylation was shown to be also dependent on signaling molecules such as eNOS and AMPK [109]. 4. Reactive astrocytes, the BBB, and immune cell infiltration The role of astrocytes at the BBB during neuroinflammation has been investigated extensively due to the importance of astrocyte–endothelial interaction in the healthy CNS (Fig. 3). If we consider the astrocyte as a product of its environment, a healthy CNS already provides numerous different microenvironments for astrocytes to react to. Besides their close interaction with the endothelial cells of the BBB, astrocytes are involved in most synaptic processes, communicate with surveilling microglia and myelinating oligodendrocytes, and are in constant contact with neighboring astrocytes through gap junctions. Neuroinflammation as observed in MS lesions highly impacts astrocyte behavior, and therefore BBB function. The process through which astrocytes respond to any CNS insult is termed astrogliosis. Although often thought of as a single uniform process, astrogliosis is better described as a spectrum of

7

changes, dictated by specific micro-environments (reviewed in [110]). In MS, astrogliosis has often been thought to contribute to lesion formation, leading to the notion that broadly inhibiting astrocyte activation is therefore desired. However, the combined outcome of many in vivo studies where astrogliosis was blocked or reactive astrocytes were abolished shows that astrogliosis is crucial for normal CNS repair, neuronal protection, BBB protection, and resolution of inflammation (reviewed in [111]). It is therefore paramount to understand the process of astrogliosis, with both beneficial and harmful effects in mind, in order to find targets for therapeutic manipulation. Reactive astrocytes are active participants in neuroinflammation, and have the capacity to produce a wide range of pro-inflammatory cytokines and chemokines that can influence BBB function and contribute to the attraction of immune cells into MS lesions. Reactive astrocytes are a notable source for the pro-inflammatory chemokine CCL2 [112], shown to be crucial in the recruitment and activation of myelindegrading macrophages. The exact moment of astrocyte activation in MS is currently difficult to pinpoint, although astrocyte activation was observed before infiltration of leukocytes in EAE [113], possibly due to the early disruption of the BBB resulting in toxic molecule entry into the CNS [114]. The pathophysiology in MS lesions results in decreased microvascular P-glycoprotein (P-gp), an ATP binding cassette (ABC) transporter that instate multi-drug resistance (MR) expression of the CNS [115, 116]. However, P-gp and MR protein-1 (MRP-1) expression is increased in reactive astrocytes in MS lesions. This increased expression of P-gp

Fig. 3. Schematic overview of perivascular astrocytes during neuroinflammation. Astrocyte endfeet terminate on the endothelial basement membrane that covers both endothelial cells and pericytes. During neuroinflammation, brain endothelial cells are immune activated and the integrity of the BBB is impaired. Breakdown of the basement membrane and loss of tight junctions and efflux transporters are illustrative for the loss of BBB function. The resulting extravasation of immune cells into the perivascular space and brain parenchyma also leads to the activation of astrocytes. Reactive astrocytes are known to contribute to BBB disruption, by secreting chemokines (CCL2), enhancing basement membrane breakdown (MMP9), and guiding migrating leukocytes into the CNS parenchyma (CS-1). Conversely, reactive astrocytes actively attenuate BBB breakdown by the secretion of BBB trophic factors (RA, Shh), controlling lymphocyte numbers (CD95L), and limiting lymphocyte extravasation (osteonectin).

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

8

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

and MRP-1 was found to mediate the release of CCL2 under inflammatory conditions, leading to enhanced migration of monocytes across the activated BBB [115]. A likely mediating mechanism was proposed, wherein pro-inflammatory bio-active lipids transported by P-gp may induce the activation of CCL2 release in an autocrine fashion [117]. The active involvement of astrocyte-derived CCL2 in immune cell infiltration has also been confirmed in vivo [118]. Besides attracting leukocytes to the lesion, reactive astrocyte-derived CCL2 might also directly influence BECs by inducing TJ-complex degradation and a consequent disruption of barrier integrity [119]. Further loss of BBB integrity might be the result of the activation of matrix metalloproteinases (MMPs) that can degrade the glia limitans during neuroinflammation. Blocking MMP-activity with fluoxetine after spinal cord injury resulted in the prevention of BBB disruption, as well as reduced infiltration of immune cells in vivo [120]. Reactive astrocytes are known to increase MMP9 expression [121], further implicating reactive gliosis in the breakdown of glia limitans-specific ECM and reduced astrocyte endfeet anchoring to the basement membrane [122]. Once activated leukocytes cross the glia limitans and invade the CNS parenchyma, reactive astrocytes are thought to facilitate their migration by interacting with leukocyte-integrins through the expression of VCAM-1 in EAE [123], and the expression of a splice variant of fibronectin, connectin segment-1 (CS-1), detectable in astrocytes at MS lesion rims [124]. Based on the alterations described for reactive astrocytes, it seems that these cells drive the neuroinflammatory damage of the BBB in MS lesions. As a consequence, dampening reactive gliosis in MS might halt BBB disruption as well as disease progression. However, in an animal model where reactive, proliferating astrocytes where specifically ablated during EAE pathogenesis, the protective and inflammation-regulatory role of reactive astrocytes was clearly demonstrated [125]. Animals that lacked an astroglial response to neuroinflammation in EAE showed increased disease progression and severity and increased numbers of CNS-infiltrated immune cells. The astrocytic response to neuroinflammation is however not restricted to detrimental effects on the surrounding cells, but also reflects protective aspects in CNS inflammation. Therefore, dampening the reactive state of astrocytes to reduce detrimental effects, might also result in the reduction of protective and anti-inflammatory effects, necessary for regeneration and repair. Protective or immune-dampening effects of reactive astrocytes have been described on various facets of neuroinflammation. Astrocytes at the BBB are known to induce T-cell apoptosis via the expression of death ligand CD95L on perivascular endfeet [126], the release of astrocyte-derived immune suppressor factor [127], and the generation of osteonectin-containing ECM [127]. Furthermore, perivascular scar formation by reactive gliosis was proposed as a mechanism to limit immune cell infiltration and thereby ongoing neuroinflammation in MS lesions [128]. Interestingly, developmental pathways involved in BBB development are now emerging as possible protective mechanisms to reduce BBB damage in neuroinflammation, as recently illustrated by the increased expression of Sonic hedge hog (Shh) by reactive astrocytes in MS lesions [129]. Shh-signaling results in inflammation-dampening effects at the BBB, and also shows barrier-enhancing properties. Recent findings also show that retinoic acid (RA) synthesis by astrocytes re-emerges during neuroinflammation in MS pathology [130], pinpointing RA as an anti-inflammatory signaling molecule released by reactive astrocytes in response to inflammation. RA is capable of dampening endothelial immune activation in vitro, by reducing inflammation-induced expression of CAMs, pro-inflammatory cytokines and chemokines, loss barrier resistance, and ROS production. RA has further been shown to possess potent anti-inflammatory actions on astrocytes and microglia [131], shows neuroprotective effects in the CNS under neuroinflammatory conditions [132], and reduces EAE clinical signs [133]. RA-signaling in the CNS therefore represents an interesting endogenous protective mechanism with therapeutic potential. Interestingly, a recent report described an inverse correlation between serum retinol levels and newly formed

Gd-enhancing lesions in relapsing–remitting MS patients [134]. Although reports are conflicting [135], the notion that increasing bioavailability of the precursor for RA might limit lesion formation is intriguing. 5. Perspectives In recent years, it has become apparent that a pro-inflammatory environment activates mechanisms in astrocytes that exacerbate neuroinflammation, but also induces protective pathways with inflammationdampening effects. Because this apparent dual role of reactive astrocytes will become an important factor to consider when thinking of astrocytes as therapeutic targets, research within this field will have to focus on the simultaneous investigation of both sides of the inflammatory cascade. Although the direct effect of reactive astrocytes or gliotic scar formation on BBB function was not addressed, it seems that astrocyte activation can both contribute to and dampen neuroinflammation in EAE, and possibly stroke. Therefore, a clear consensus on what comprises a reactive astrocytes, either in MS and or after an ischemic stroke, is needed to distinguish between the early response to inflammation and a possible late response involved in lesion containment and scar formation. This especially holds true for in vitro studies of astrocyte behavior, where various inflammatory mediators lead to different reactive astrocyte phenotypes and their resulting impact on the BBB endothelium. Furthermore, the association of other pathways that have been associated with BBB development, the Wnt/β-catenin pathway [136,137] and the early association of CNS pericytes with the developing BBB [138], with MS or EAE pathology or in experimental stroke models remains to be investigated. Restarting developmental programs at the disrupted BBB might be an intrinsic mechanism to reinstate the barrier during or after neuroinflammation. Unraveling ways of boosting this self-regenerative capacity of the CNS to repair BBB disruption shows significant promise as a possible novel therapeutic avenue in MS. Moreover, a more clear definition of the role of the different brain barriers in the immune cell trafficking processes after a stroke and during MS needs to be further elucidated. In the search for common denominators that occur in both the diseases, the recent view that cerebral hypoperfusion [139] as a new pathological concept in MS is of interest. As a consequence, hypoxia may occur and lead to severe oxidative stress, which is a pathological hallmark of MS (reviewed in Ref. [140]) and stroke [141]. Vice versa, the effects of DMT that are currently approved for MS on patients after a stroke are of high interest. Conflict of interest statement The authors have no conflicts of interest to declare. References [1] R. Milo, A. Miller, Revised diagnostic criteria of multiple sclerosis, Autoimmun. Rev. 13 (2014) 518. [2] R.W. Orrell, Multiple sclerosis: the history of a disease, J. R. Soc. Med. 98 (2005) 289. [3] I. Loma, R. Heyman, Multiple sclerosis: pathogenesis and treatment, Curr. Neuropharmacol. 9 (2011) 409. [4] B.V. Zlokovic, The blood–brain barrier in health and chronic neurodegenerative disorders, Neuron 57 (2008) 178. [5] B.G. Weinshenker, B. Bass, G.P.A. Rice, J. Noseworthy, W. Carriere, J. Baskerville, G.C. Ebers, The natural history of multiple sclerosis: a geographically based study I. Clinical course and disability, Brain 112 (1989) 133. [6] M. Sospedra, R. Martin, Immunology of multiple sclerosis, Annu. Rev. Immunol. 23 (2005) 683. [7] H. Babbe, A. Roers, A. Waisman, H. Lassmann, N. Goebels, R. Hohlfeld, M. Friese, R. Schröder, M. Deckert, S. Schmidt, Clonal expansions of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction, J. Exp. Med. 192 (2000) 393. [8] J.I. Alvarez, R. Cayrol, A. Prat, Disruption of central nervous system barriers in multiple sclerosis, Biochim. Biophys. Acta (BBA) - Mol. Basis Dis. 1812 (2011) 252. [9] S.V. Ramagopalan, R. Dobson, U.C. Meier, G. Giovannoni, Multiple sclerosis: risk factors, prodromes, and potential causal pathways, Lancet Neurol. 9 (2010) 727.

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx [10] B.D. Trapp, J. Peterson, R.M. Ransohoff, R. Rudick, S. Mörk, L. Bö, Axonal transection in the lesions of multiple sclerosis, N. Engl. J. Med. 338 (1998) 278. [11] T. Scheikl, B. Pignolet, L.T. Mars, R.S. Liblau, Transgenic mouse models of multiple sclerosis, Cell. Mol. Life Sci. 67 (2010) 4011. [12] J.M. Fletcher, S.J. Lalor, C.M. Sweeney, N. Tubridy, K.H.G. Mills, T cells in multiple sclerosis and experimental autoimmune encephalomyelitis, Clin. Exp. Immunol. 162 (2010) 1. [13] C.L. Langrish, Y. Chen, W.M. Blumenschein, J. Mattson, B. Basham, J.D. Sedgwick, T. McClanahan, R.A. Kastelein, D.J. Cua, IL-23 drives a pathogenic T cell population that induces autoimmune inflammation, J. Exp. Med. 201 (2005) 233. [14] M. Pette, K. Fujita, B. Kitze, J.N. Whitaker, E. Albert, L. Kappos, H. Wekerle, Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals, Neurology 40 (1990) 1770. [15] Y. Cao, B.A. Goods, K. Raddassi, G.T. Nepom, W.W. Kwok, J.C. Love, D.A. Hafler, Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis, Sci. Transl. Med. 7 (2015) (287ra74). [16] K. Venken, N. Hellings, K. Hensen, J.-L. Rummens, R. Medaer, M.B. D'hooghe, B. Dubois, J. Raus, P. Stinissen, Secondary progressive in contrast to relapsing–remitting multiple sclerosis patients show a normal CD4+ CD25+ regulatory T-cell function and FOXP3 expression, J. Neurosci. Res. 83 (2006) 1432. [17] V. Viglietta, C. Baecher-Allan, H.L. Weiner, D.A. Hafler, Loss of functional suppression by CD4+ CD25 + regulatory T cells in patients with multiple sclerosis, J. Exp. Med. 199 (2004) 971. [18] A. Schneider, S.A. Long, K. Cerosaletti, C.T. Ni, P. Samuels, M. Kita, J.H. Buckner, In active relapsing–remitting multiple sclerosis, effector T cell resistance to adaptive Tregs involves IL-6-mediated signaling, Sci. Transl. Med. 5 (2013) (170ra15). [19] P.K. Stys, G.W. Zamponi, J. van Minnen, J.J. Geurts, Will the real multiple sclerosis please stand up? Nat. Rev. Neurosci. 13 (2012) 507. [20] R. Bhat, L. Steinman, Innate and adaptive autoimmunity directed to the central nervous system, Neuron 64 (2009) 123. [21] M.H. Barnett, J.W. Prineas, Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion, Ann. Neurol. 55 (2004) 458. [22] M. Rodriguez, B. Scheithauer, Ultrastructure of multiple sclerosis, Ultrastruct. Pathol. 18 (1994) 3. [23] P.D. Molyneux, L. Kappos, C. Polman, C. Pozzilli, F. Barkhof, M. Filippi, T. Yousry, D. Hahn, K. Wagner, M. Ghazi, The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis, Brain 123 (2000) 2256. [24] K. Hawker, Progressive multiple sclerosis: characteristics and management, Neurol. Clin. 29 (2011) 423. [25] S. Harbison, Cell therapy for multiple sclerosis: a new hope, Biosci. Horiz. 7 (2014) (hzu014). [26] C. Sheridan, Third oral MS drug wins FDA nod, Nat. Biotechnol. 31 (2013) 373. [27] K.P. Johnson, B.R. Brooks, J.A. Cohen, C.C. Ford, J. Goldstein, R.P. Lisak, L.W. Myers, H.S. Panitch, J.W. Rose, R.B. Schiffer, Copolymer 1 reduces relapse rate and improves disability in relapsing–remitting multiple sclerosis results of a phase III multicenter, double-blind, placebo-controlled trial, Neurology 45 (1995) 1268. [28] S. Dhib-Jalbut, S. Marks, Interferon-β mechanisms of action in multiple sclerosis, Neurology 74 (2010) S17–S24. [29] C.A. McGraw, F.D. Lublin, Interferon beta and glatiramer acetate therapy, Neurotherapeutics 10 (2013) 2. [30] M.K. Racke, A.E. Lovett-Racke, N.J. Karandikar, The mechanism of action of glatiramer acetate treatment in multiple sclerosis, Neurology 74 (2010) S25–S30. [31] B.C. Kieseier, H. Wiendl, New evidence for teriflunomide in multiple sclerosis, Lancet Neurol. 13 (2014) 234. [32] J.G. Cyster, Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs, Annu. Rev. Immunol. 23 (2005) 127. [33] V. Brinkmann, FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system, Br. J. Pharmacol. 158 (2009) 1173. [34] P. Albrecht, I. Bouchachia, N. Goebels, N. Henke, H.H. Hofstetter, A. Issberner, Z. Kovacs, J. Lewerenz, D. Lisak, P. Maher, Effects of dimethyl fumarate on neuroprotection and immunomodulation, J. Neuroinflammation 9 (2012) 2094. [35] A. Bar-Or, A. Pachner, F. Menguy-Vacheron, J. Kaplan, H. Wiendl, Teriflunomide and its mechanism of action in multiple sclerosis, Drugs 74 (2014) 659. [36] U. Dirnagl, M. Endres, Found in translation preclinical stroke research predicts human pathophysiology, clinical phenotypes, and therapeutic outcomes, Stroke 45 (2014) 1510. [37] J. Zhang, Y. Zhang, S. Xing, Z. Liang, J. Zeng, Secondary neurodegeneration in remote regions after focal cerebral infarction a new target for stroke management? Stroke 43 (2012) 1700. [38] S. Love, D. Louis, D.W. Ellison, Greenfield's Neuropathology Eighth Edition 2Volume Set, CRC Press, 2008. [39] J. Aronowski, R. Strong, J.C. Grotta, Reperfusion injury: demonstration of brain damage produced by reperfusion after transient focal ischemia in rats, J. Cereb. Blood Flow Metab. 17 (1997) 1048. [40] D.F. Emerich, R.L. Dean, R.T. Bartus, The role of leukocytes following cerebral ischemia: pathogenic variable or bystander reaction to emerging infarct? Exp. Neurol. 173 (2002) 168. [41] I. Perez-de-Puig, F. Miró-Mur, M. Ferrer-Ferrer, E. Gelpi, J. Pedragosa, C. Justicia, X. Urra, A. Chamorro, A.M. Planas, Neutrophil recruitment to the brain in mouse and human ischemic stroke, Acta Neuropathol. 129 (2015) 239. [42] G. Enzmann, C. Mysiorek, R. Gorina, Y.J. Cheng, S. Ghavampour, M.J. Hannocks, V. Prinz, U. Dirnagl, M. Endres, M. Prinz, The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury, Acta Neuropathol. 125 (2013) 395.

9

[43] M. Gliem, A.K. Mausberg, J.-I. Lee, I. Simiantonakis, N. van Rooijen, H.-P. Hartung, S. Jander, Macrophages prevent hemorrhagic infarct transformation in murine stroke models, Ann. Neurol. 71 (2012) 743. [44] O.B. Dimitrijevic, S.M. Stamatovic, R.F. Keep, A.V. Andjelkovic, Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice, Stroke 38 (2007) 1345. [45] S.G. Soriano, L.S. Amaravadi, Y.F. Wang, H. Zhou, X.Y. Gary, J.R. Tonra, V. FairchildHuntress, Q. Fang, J.H. Dunmore, D. Huszar, Mice deficient in fractalkine are less susceptible to cerebral ischemia–reperfusion injury, J. Neuroimmunol. 125 (2002) 59. [46] M. Lalancette-Hérbert, G. Gowing, A. Simard, Y.C. Weng, J. Kriz, Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain, J. Neurosci. 27 (2007) 2596. [47] C. Kleinschnitz, P. Kraft, A. Dreykluft, I. Hagedorn, K. Göbel, M.K. Schuhmann, F. Langhauser, X. Helluy, T. Schwarz, S. Bittner, Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature, Blood 121 (2013) 679. [48] A. Liesz, E. Suri-Payer, C. Veltkamp, H. Doerr, C. Sommer, S. Rivest, T. Giese, R. Veltkamp, Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke, Nat. Med. 15 (2009) 192. [49] K.P. Doyle, L.N. Quach, M. Solé, R.C. Axtell, T.V. Nguyen, G.J. Soler-Llavina, S. Jurado, J. Han, L. Steinman, F.M. Longo, B-lymphocyte-mediated delayed cognitive impairment following stroke, J. Neurosci. 35 (2015) 2133. [50] X. Ren, K. Akiyoshi, S. Dziennis, A.A. Vandenbark, P.S. Herson, P.D. Hurn, H. Offner, Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke, J. Neurosci. 31 (2011) 8556. [51] E.S. Connolly Jr., C.J. Winfree, T.A. Springer, Y. Naka, H. Liao, S.D. Yan, D.M. Stern, R.A. Solomon, J.C. Gutierrez-Ramos, D.J. Pinsky, Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke, J. Clin. Investig. 97 (1996) 209. [52] Enlimomab Acute Stroke Trial Investigators, Use of anti-ICAM-1 therapy in ischemic stroke results of the Enlimomab Acute Stroke Trial, Neurology 57 (2001) 1428. [53] K.J. Becker, Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6. 5) in acute stroke, Curr. Med. Res. Opin. 18 (2002) s18–s22. [54] K. Furuya, H. Takeda, S. Azhar, R.M. McCarron, Y. Chen, C.A. Ruetzler, K.M. Wolcott, T.J. DeGraba, R. Rothlein, T.E. Hugli, Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine antihuman intercellular adhesion molecule-1 antibody a bedside-to-bench study, Stroke 32 (2001) 2665. [55] H. Xu, J.A. Gonzalo, Y.S. Pierre, I.R. Williams, T.S. Kupper, R.S. Cotran, T.A. Springer, J.C. Gutierrez-Ramos, Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice, J. Exp. Med. 180 (1994) 95. [56] J.E. Sligh, C.M. Ballantyne, S.S. Rich, H.K. Hawkins, C.W. Smith, A. Bradley, A.L. Beaudet, Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1, Proc. Natl. Acad. Sci. 90 (1993) 8529. [57] N.K. van den Engel, E. Heidenthal, A. Vinke, H. Kolb, S. Martin, Circulating forms of intercellular adhesion molecule (ICAM)-1 in mice lacking membranous ICAM-1, Blood 95 (2000) 1350. [58] P. Rieckmann, U. Michel, M. Albrecht, W. Brück, L. Wöckel, K. Felgenhauer, Soluble forms of intercellular adhesion molecule-1 (ICAM-1) block lymphocyte attachment to cerebral endothelial cells, J. Neuroimmunol. 60 (1995) 9. [59] X. Hu, S.R. Barnum, J.E. Wohler, T.R. Schoeb, D.C. Bullard, Differential ICAM-1 isoform expression regulates the development and progression of experimental autoimmune encephalomyelitis, Mol. Immunol. 47 (2010) 1692. [60] J. Neumann, M. Riek-Burchardt, J. Herz, T.R. Doeppner, R. König, H. Hütten, E. Etemire, L. Männ, A. Klingberg, T. Fischer, M.W. Görtler, H.-J. Heinze, P. Reichardt, B. Schraven, D.M. Hermann, K.G. Reymann, M. Gunzer, Very-late-antigen-4 (VLA4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke, Acta Neuropathol. 129 (2015) 259. [61] A. Liesz, W. Zhou, É. Mracskó, S. Karcher, H. Bauer, S. Schwarting, L. Sun, D. Bruder, S. Stegemann, A. Cerwenka, Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke, Brain 134 (2011) 704. [62] F. Langhauser, P. Kraft, E. Göb, J. Leinweber, M.K. Schuhmann, K. Lorenz, M. Gelderblom, S. Bittner, S.G. Meuth, H. Wiendl, Blocking of α4 integrin does not protect from acute ischemic stroke in mice, Stroke 45 (2014) 1799. [63] G. Llovera, K. Hofmann, S. Roth, A. Salas-Pérdomo, M. Ferrer-Ferrer, C. Perego, E.R. Zanier, U. Mamrak, A. Rex, H. Party, V. Agin, C. Fauchon, C. Orset, B. Haelewyn, M.G. De Simoni, U. Dirnagl, U. Grittner, A.M. Planas, N. Plesnila, D. Vivien, A. Liesz, Results of a preclinical randomized controlled multicenter trial (pRCT): anti-CD49d treatment for acute brain ischemia, Sci. Transl. Med. 7 (2015) (299ra121). [64] C.F. Barker, R.E. Billingham, Immunologically privileged sites, Adv. Immunol. 25 (1978) 1. [65] I. Galea, I. Bechmann, V.H. Perry, What is immune privilege (not)? Trends Immunol. 28 (2007) 12. [66] B. Engelhardt, C. Coisne, Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle, Fluids Barriers CNS 8 (2011) 10. [67] S.S. Ousman, P. Kubes, Immune surveillance in the central nervous system, Nat. Neurosci. 15 (2012) 1096. [68] J.D. Laman, R.O. Weller, Drainage of cells and soluble antigen from the CNS to regional lymph nodes, J. NeuroImmune Pharmacol. 8 (2013) 840. [69] G. Kunis, K. Baruch, O. Miller, M. Schwartz, Immunization with a myelin-derived antigen activates the brain's choroid plexus for recruitment of immunoregulatory cells to the CNS and attenuates disease progression in a mouse model of ALS, J. Neurosci. 35 (2015) 6381.

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

10

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx

[70] S. Cepok, M. Jacobsen, S. Schock, B. Omer, S. Jaekel, I. Böddeker, W.H. Oertel, N. Sommer, B. Hemmer, Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis, Brain 124 (2001) 2169. [71] C. Raposo, N. Graubardt, M. Cohen, C. Eitan, A. London, T. Berkutzki, M. Schwartz, CNS repair requires both effector and regulatory T cells with distinct temporal and spatial profiles, J. Neurosci. 34 (2014) 10141. [72] R.B. Meeker, K. Williams, D.A. Killebrew, L.C. Hudson, Cell trafficking through the choroid plexus, Cell Adhes. Migr. 6 (2012) 390. [73] W.W. Unger, S. Laban, F.S. Kleijwegt, A.R. van der Slik, B.O. Roep, Induction of treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1, Eur. J. Immunol. 39 (2009) 3147. [74] K. Baruch, N. Ron-Harel, H. Gal, A. Deczkowska, E. Shifrut, W. Ndifon, N. MirlasNeisberg, M. Cardon, I. Vaknin, L. Cahalon, CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging, Proc. Natl. Acad. Sci. 110 (2013) 2264. [75] B. Engelhardt, L. Sorokin, The Blood–Brain and the Blood–Cerebrospinal Fluid Barriers: Function and Dysfunction, Springer, 2009 497–511. [76] G. Kooij, K. Kopplin, R. Blasig, M. Stuiver, N. Koning, G. Goverse, S.M. van der Pol, B. van het Hof, M. Gollasch, J.A. Drexhage, Disturbed function of the blood–cerebrospinal fluid barrier aggravates neuro-inflammation, Acta Neuropathol. 128 (2014) 267. [77] R.M. Ransohoff, Immunology: in the beginning, Nature 462 (2009) 41. [78] A. Reboldi, C. Coisne, D. Baumjohann, F. Benvenuto, D. Bottinelli, S. Lira, A. Uccelli, A. Lanzavecchia, B. Engelhardt, F. Sallusto, CC chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE, Nat. Immunol. 10 (2009) 514. [79] B. Engelhardt, K. Wolburg-Buchholz, H. Wolburg, Involvement of the choroid plexus in central nervous system inflammation, Microsc. Res. Tech. 52 (2001) 112. [80] K. Wolburg, H. Gerhardt, M. Schulz, H. Wolburg, B. Engelhardt, Ultrastructural localization of adhesion molecules in the healthy, Cell Tissue Res. 296 (1999) 259. [81] L. Battistini, L. Piccio, B. Rossi, S. Bach, S. Galgani, C. Gasperini, L. Ottoboni, D. Ciabini, M.D. Caramia, G. Bernardi, CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1, Blood 101 (2003) 4775. [82] B. Bahbouhi, L. Berthelot, S. Pettre, L. Michel, S. Wiertlewski, B. Weksler, I.A. Romero, F. Miller, P.O. Couraud, S. Brouard, Peripheral blood CD4+ T lymphocytes from multiple sclerosis patients are characterized by higher PSGL-1 expression and transmigration capacity across a human blood–brain barrier-derived endothelial cell line, J. Leukoc. Biol. 86 (2009) 1049. [83] U. Gotsch, U. Jäger, M. Dominis, D. Vestweber, Expression of P-selectin on endothelial cells is upregulated by LPS and TNF-α in vivo, Cell Commun. Adhes. 2 (1994) 7. [84] L. Piccio, B. Rossi, E. Scarpini, C. Laudanna, C. Giagulli, A.C. Issekutz, D. Vestweber, E.C. Butcher, G. Constantin, Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric Gi-linked receptors, J. Immunol. 168 (2002) 1940. [85] J. Greenwood, S.J. Heasman, J.I. Alvarez, A. Prat, R. Lyck, B. Engelhardt, Review: leucocyte-endothelial cell crosstalk at the blood–brain barrier: a prerequisite for successful immune cell entry to the brain, Neuropathol. Appl. Neurobiol. 37 (2011) 24. [86] M. Krumbholz, D. Theil, F. Steinmeyer, S. Cepok, B. Hemmer, M. Hofbauer, C. Farina, T. Derfuss, A. Junker, T. Arzberger, CCL19 is constitutively expressed in the CNS, upregulated in neuroinflammation, active and also inactive multiple sclerosis lesions, J. Neuroimmunol. 190 (2007) 72. [87] E.A. Subileau, P. Rezaie, H.A. Davies, F.M. Colyer, J. Greenwood, D.K. Male, I.A. Romero, Expression of chemokines and their receptors by human brain endothelium: implications for multiple sclerosis, J. Neuropathol. Exp. Neurol. 68 (2009) 227. [88] C. McManus, J.W. Berman, F.M. Brett, H. Staunton, M. Farrell, C.F. Brosnan, MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study, J. Neuroimmunol. 86 (1998) 20. [89] A. Prat, K. Biernacki, J.F. Lavoie, J. Poirier, P. Duquette, J.P. Antel, Migration of multiple sclerosis lymphocytes through brain endothelium, Arch. Neurol. 59 (2002) 391. [90] B.J. Steffen, E.C. Butcher, B. Engelhardt, Evidence for involvement of ICAM-1 and VCAM-1 in lymphocyte interaction with endothelium in experimental autoimmune encephalomyelitis in the central nervous system in the SJL/J mouse, Am. J. Pathol. 145 (1994) 189. [91] L. Bö, J.W. Peterson, S. Mark, P.A. Hoffman, M.W. Gallatin, R.M. Ransohoff, B.D. Trapp, Distribution of immunoglobulin superfamily members ICAM-1,-2,-3, and the β2 integrin LFA-1 in multiple sclerosis lesions, J. Neuropathol. Exp. Neurol. 55 (1996) 1060. [92] P. Vajkoczy, M. Laschinger, B. Engelhardt, α4-integrin-VCAM-1 binding mediates G protein-independent capture of encephalitogenic T cell blasts to CNS white matter microvessels, J. Clin. Invest. 108 (2001) 557. [93] J. Greenwood, Y. Wang, V.L. Calder, Lymphocyte adhesion and transendothelial migration in the central nervous system: the role of LFA-1, ICAM-1, VLA-4 and VCAM1, Immunology 86 (1995) 408. [94] I. Bartholomäus, N. Kawakami, F. Odoardi, C. Schläger, D. Miljkovic, J.W. Ellwart, W.E. Klinkert, C. Flügel-Koch, T.B. Issekutz, H. Wekerle, A. Flügel, Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions, Nature 462 (2009) 94. [95] O. Steiner, C. Coisne, R. Cecchelli, R. Boscacci, U. Deutsch, B. Engelhardt, R. Lyck, Differential roles for endothelial ICAM-1, ICAM-2, and VCAM-1 in shear-resistant T cell arrest, polarization, and directed crawling on blood–brain barrier endothelium, J. Immunol. 185 (2010) 4846. [96] L. Svensson, P. Stanley, F. Willenbrock, N. Hogg, The Gαq/11 Proteins Contribute to T Lymphocyte Migration by Promoting Turnover of Integrin LFA-1 Through Recycling, 2012.

[97] R. Evans, A.C. Lellouch, L. Svensson, A. McDowall, N. Hogg, The integrin LFA-1 signals through ZAP-70 to regulate expression of high-affinity LFA-1 on T lymphocytes, Blood 117 (2011) 3331. [98] M.P. Valignat, O. Theodoly, A. Gucciardi, N. Hogg, A.C. Lellouch, T lymphocytes orient against the direction of fluid flow during LFA-1-mediated migration, Biophys. J. 104 (2013) 322. [99] M. Abadier, N. Haghayegh Jahromi, L. Cardoso Alves, R. Boscacci, D. Vestweber, S. Barnum, U. Deutsch, B. Engelhardt, R. Lyck, Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood–brain barrier, Eur. J. Immunol. 45 (2015) 1043. [100] B. Engelhardt, R.M. Ransohoff, Capture, crawl, cross: the T cell code to breach the blood-brain barriers, Trends in Immunol. 33 (2012) 579. [101] Z. Shulman, V. Shinder, E. Klein, V. Grabovsky, O. Yeger, E. Geron, A. Montresor, M. Bolomini-Vittori, S.W. Feigelson, T. Kirchhausen, Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin, Immunity 30 (2009) 384. [102] E.S. Wittchen, Endothelial signaling in paracellular and transcellular leukocyte transmigration, Front. Biosci.: J. Virtual Libr. 14 (2009) 2522. [103] O. Durieu-Trautmann, N. Chaverot, S. Cazaubon, A.D. Strosberg, P.O. Couraud, Intercellular adhesion molecule 1 activation induces tyrosine phosphorylation of the cytoskeleton-associated protein cortactin in brain microvessel endothelial cells, J. Biol. Chem. 269 (1994) 12536. [104] S. Etienne-Manneville, J.B. Manneville, P. Adamson, B. Wilbourn, J. Greenwood, P.O. Couraud, ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines, J. Immunol. 165 (2000) 3375. [105] S. Etienne, P. Adamson, J. Greenwood, A.D. Strosberg, S. Cazaubon, P.O. Couraud, ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells, J. Immunol. 161 (1998) 5755. [106] J. Greenwood, C.L. Amos, C.E. Walters, P.O. Couraud, R. Lyck, B. Engelhardt, P. Adamson, Intracellular domain of brain endothelial intercellular adhesion molecule-1 is essential for T lymphocyte-mediated signaling and migration, J. Immunol. 171 (2003) 2099. [107] R. Lyck, Y. Reiss, N. Gerwin, J. Greenwood, P. Adamson, B. Engelhardt, T-cell interaction with ICAM-1/ICAM-2 double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells, Blood 102 (2003) 3675. [108] P. Turowski, R. Martinelli, R. Crawford, D. Wateridge, A.P. Papageorgiou, M.G. Lampugnani, A.C. Gamp, D. Vestweber, P. Adamson, E. Dejana, Phosphorylation of vascular endothelial cadherin controls lymphocyte emigration, J. Cell Sci. 121 (2008) 29. [109] R. Martinelli, M. Gegg, R. Longbottom, P. Adamson, P. Turowski, J. Greenwood, ICAM-1-mediated endothelial nitric oxide synthase activation via calcium and AMP-activated protein kinase is required for transendothelial lymphocyte migration, Mol. Biol. Cell 20 (2009) 995. [110] M.A. Anderson, Y. Ao, M.V. Sofroniew, Heterogeneity of reactive astrocytes, Neurosci. Lett. 565 (2014) 23. [111] M.V. Sofroniew, Astrocyte barriers to neurotoxic inflammation, Nat. Rev. Neurosci. 16 (2015) 249. [112] P. Van Der Voorn, J. Tekstra, R.H. Beelen, C.P. Tensen, P. van der Valk, C.J. De Groot, Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions, Am. J. Pathol. 154 (1999) 45. [113] F.E. D'Amelio, M.E. Smith, L.F. Eng, Sequence of tissue responses in the early stages of experimental allergic encephalomyelitis (EAE): immunohistochemical, light microscopic, and ultrastructural observations in the spinal cord, Glia 3 (1990) 229. [114] D. Wang, M.M. Ayers, D.V. Catmull, L.J. Hazelwood, C.C. Bernard, J.M. Orian, Astrocyte-associated axonal damage in pre-onset stages of experimental autoimmune encephalomyelitis, Glia 51 (2005) 235. [115] G. Kooij, M.R. Mizee, J. van Horssen, A. Reijerkerk, M.E. Witte, J.A. Drexhage, S.M. van der Pol, B. van het Hof, G. Scheffer, R. Scheper, Adenosine triphosphatebinding cassette transporters mediate chemokine (CC motif) ligand 2 secretion from reactive astrocytes: relevance to multiple sclerosis pathogenesis, Brain (2010) (awq330). [116] G. Kooij, J. van Horssen, E.C. de Lange, A. Reijerkerk, S.M. van der Pol, B. van het Hof, J. Drexhage, A. Vennegoor, J. Killestein, G. Scheffer, T lymphocytes impair Pglycoprotein function during neuroinflammation, J. Autoimmun. 34 (2010) 416. [117] G. Kooij, J. van Horssen, V.V.R. Bandaru, N.J. Haughey, H.E. de Vries, The role of ATPbinding cassette transporters in neuro-inflammation: relevance for bioactive lipids, Front. Pharmacol. 3 (2012). [118] S. Ge, B. Shrestha, D. Paul, C. Keating, R. Cone, A. Guglielmotti, J.S. Pachter, The CCL2 synthesis inhibitor bindarit targets cells of the neurovascular unit, and suppresses experimental autoimmune encephalomyelitis, J. Neuroinflammation 9 (2012) 171. [119] S.M. Stamatovic, R.F. Keep, M.M. Wang, I. Jankovic, A.V. Andjelkovic, Caveolaemediated internalization of occludin and claudin-5 during CCL2-induced tight junction remodeling in brain endothelial cells, J. Biol. Chem. 284 (2009) 19053. [120] J.Y. Lee, H.S. Kim, H.Y. Choi, T.H. Oh, T.Y. Yune, Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury, Brain (2012) (aws171). [121] H.R. Ranaivo, J.N. Hodge, N. Choi, M.S. Wainwright, Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen speciesdependent pathways, J. Neuroinflammation 9 (2012) 1. [122] S. Agrawal, P. Anderson, M. Durbeej, N. van Rooijen, F. Ivars, G. Opdenakker, L.M. Sorokin, Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis, J. Exp. Med. 203 (2006) 1007.

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018

M.A. Lopes Pinheiro et al. / Biochimica et Biophysica Acta xxx (2015) xxx–xxx [123] M.A. Gimenez, J.E. Sim, J.H. Russell, TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation, J. Neuroimmunol. 151 (2004) 116. [124] J. van Horssen, L. Bo, C.M. Vos, I. Virtanen, H.E. de Vries, Basement membrane proteins in multiple sclerosis-associated inflammatory cuffs: potential role in influx and transport of leukocytes, J. Neuropathol. Exp. Neurol. 64 (2005) 722. [125] R.R. Voskuhl, R.S. Peterson, B. Song, Y. Ao, L.B. Morales, S. Tiwari-Woodruff, M.V. Sofroniew, Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS, J. Neurosci. 29 (2009) 11511. [126] I. Bechmann, B. Steiner, U. Gimsa, G. Mor, S. Wolf, M. Beyer, R. Nitsch, F. Zipp, Astrocyte-induced T cell elimination is CD95 ligand dependent, J. Neuroimmunol. 132 (2002) 60. [127] H. Hara, Y. Nanri, E. Tabata, S. Mitsutake, T. Tabira, Identification of astrocytederived immune suppressor factor that induces apoptosis of autoreactive T cells, J. Neuroimmunol. 233 (2011) 135. [128] H. Mohan, M. Krumbholz, R. Sharma, S. Eisele, A. Junker, M. Sixt, J. Newcombe, H. Wekerle, R. Hohlfeld, H. Lassmann, Extracellular matrix in multiple sclerosis lesions: fibrillar collagens, biglycan and decorin are upregulated and associated with infiltrating immune cells, Brain Pathol. 20 (2010) 966. [129] J.I. Alvarez, A. Dodelet-Devillers, H. Kebir, I. Ifergan, P.J. Fabre, S. Terouz, M. Sabbagh, K. Wosik, L. Bourbonnière, M. Bernard, The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence, Science 334 (2011) 1727. [130] M.R. Mizee, P.G. Nijland, S.M. van der Pol, J.A. Drexhage, B. van het Hof, R. Mebius, P. van der Valk, J. van Horssen, A. Reijerkerk, H.E. de Vries, Astrocyte-derived retinoic acid: a novel regulator of blood–brain barrier function in multiple sclerosis, Acta Neuropathol. 128 (2014) 691. [131] J. Xu, P.D. Drew, 9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytes, J. Neuroimmunol. 171 (2006) 135. [132] H. Katsuki, E. Kurimoto, S. Takemori, Y. Kurauchi, A. Hisatsune, Y. Isohama, Y. Izumi, T. Kume, K. Shudo, A. Akaike, Retinoic acid receptor stimulation protects midbrain

[133]

[134]

[135] [136]

[137]

[138] [139]

[140]

[141]

11

dopaminergic neurons from inflammatory degeneration via BDNF-mediated signaling, J. Neurochem. 110 (2009) 707. C. Klemann, B.J. Raveney, A.K. Klemann, T. Ozawa, S. von Horsten, K. Shudo, S. Oki, T. Yamamura, Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis, Am. J. Pathol. 174 (2009) 2234. K.I. Løken-Amsrud, K.M. Myhr, S.J. Bakke, A.G. Beiske, K.S. Bjerve, B.T. Bjørnarå, H. Hovdal, F. Lilleås, R. Midgard, T. Pedersen, Retinol levels are associated with magnetic resonance imaging outcomes in multiple sclerosis, Mult. Scler. J. (2012) (1352458512457843). T.F. Runia, W.C.J. Hop, Y.B. de Rijke, R.Q. Hintzen, Vitamin A is not associated with exacerbations in multiple sclerosis, Mult. Scler. Relat. Disord. 3 (2014) 34. S. Liebner, M. Corada, T. Bangsow, J. Babbage, A. Taddei, C.J. Czupalla, M. Reis, A. Felici, H. Wolburg, M. Fruttiger, Wnt/β-catenin signaling controls development of the blood–brain barrier, J. Cell Biol. 183 (2008) 409. R. Daneman, D. Agalliu, L. Zhou, F. Kuhnert, C.J. Kuo, B.A. Barres, Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis, Proc. Natl. Acad. Sci. 106 (2009) 641. R. Daneman, L. Zhou, A.A. Kebede, B.A. Barres, Pericytes are required for blood– brain barrier integrity during embryogenesis, Nature 468 (2010) 562. M. D'haeseleer, S. Hostenbach, I. Peeters, S. El Sankari, G. Nagels, J. De Keyser, M.B. D'hooghe, Cerebral hypoperfusion: a new pathophysiologic concept in multiple sclerosis? J. Cereb. Blood Flow Metab. (2015). J. van Horssen, M.E. Witte, G. Schreibelt, H.E. de Vries, Radical changes in multiple sclerosis pathogenesis, Biochim. Biophys. Acta (BBA) — Mol. Basis Dis. 1812 (2011) 141. S. Fazel Nabavi, M. Dean, A. Turner, A. Sureda, M. Daglia, S. Mohammad Nabavi, Oxidative stress and post-stroke depression: possible therapeutic role of polyphenols? Curr. Med. Chem. 22 (2015) 343.

Please cite this article as: M.A. Lopes Pinheiro, et al., Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/j.bbadis.2015.10.018