Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Fabis, Marzena J.; Scott, G.; Kean, Rhonda; Koprowski, Hilary; Hooper, D. Craig

doi:10.1073/pnas.0701252104

Cited by 89 publications

(59 citation statements)

References 44 publications

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“…In recent studies the extent of BSCB disruption was shown to correlate with the severity of EAE, as measured by fluorometric analyses of whole homogenized spinal cords (55,73). In the present study, we did not find a direct correlation between the level of BSCB permeability and clinical score, but rather with the day of disease onset.…”

Section: Discussioncontrasting

confidence: 49%

“…Hence, in our hands the EAE score is only partially related to the extent of BSCB disruption in the lumbar spinal cord and as such is not the optimal point of reference for reporting BSCB permeability. This slightly differs from other studies reporting a correlation between clinical severity and the extent of BSCB disruption, although they used different assays, immunization protocols, or mouse strains (4,55).…”

Section: Bscb Disruption Is Transient and Initiated Shortly Before Eacontrasting

confidence: 50%

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Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Aubé

Lévesque

Paré

et al. 2014

The Journal of Immunology

186

159

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Disruption of the blood–brain and blood–spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP+ myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP+ cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

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Section: Discussioncontrasting

confidence: 49%

Section: Bscb Disruption Is Transient and Initiated Shortly Before Eacontrasting

confidence: 50%

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Aubé

Lévesque

Paré

et al. 2014

The Journal of Immunology

186

159

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“…A pivotal step in triggering of CNS inflammation is disruption of the blood-brain barrier (BBB) (25). We, therefore, next administered the EP4 agonist to mice from days 7 to 14, injected sodium fluorescein intraperitoneally on day 14, and then, quantified fluorescein incorporation into the spinal cord 30 min later.…”

Section: Resultsmentioning

confidence: 99%

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Esaki

Li²,

Sakata³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

106

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Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4 −/− mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2 −/− mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2 −/− mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE 2 exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood-brain barrier through EP4.disease model | knockout mice | prostaglandin | prostaglandin receptor | multiple sclerosis M ultiple sclerosis (MS) is a chronic inflammatory disease of the CNS that primarily affects young adults (1, 2). The main pathological characteristics of MS include cell infiltration, demyelination, and axonal loss in the CNS. Although its etiology remains unclear, MS is thought to be a T cell-mediated autoimmune disease of the CNS in genetically susceptible individuals. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that can be induced in susceptible animals by immunization with myelin proteins or by injection of myelin proteinspecific CD4 + T cells (3). EAE has been studied intensively in investigations of the autoimmune response in the CNS, with recent studies having shown that T effector helper (Th) 17 or both Th17 and Th1 cells play a key role in disease pathogenesis (4-6). These Th cell subsets are also implicated in human MS (7-9).The concentrations of arachidonate metabolites such as prostaglandin (PG) E 2 and leukotriene C 4 are increased in the cerebrospinal fluid (CSF) of individuals with MS (10, 11). Arachidonic acid is liberated from phospholipids by the action of phospholipase A 2 and converted to PGs or leukotrienes by the action of cyclooxygenase (COX) and 5-lipoxygenase, respectively. Cytosolic phospholipase A 2 is a major form of phospholipase A 2 that is activated and liberates a...

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“…Both knockout strains bear an H-2b haplotype, which confers susceptibility to MOG -induced EAE. However, Prl 2/2 mice were backcrossed into C57BL/6 background, which is known to be more susceptible to EAE development than the 129 background, into which Prlr 2/2 mice were backcrossed (26,27). All procedures involving animals were approved by the Institute Ethical Committee and performed in accordance to institutional guidelines and national law (DL116/92), and carried out according to the Principles of Laboratory Animal Care (European Communities Council Directive 86/609/EEC).…”

Section: Micementioning

confidence: 99%

Prolactin Is Not Required for the Development of Severe Chronic Experimental Autoimmune Encephalomyelitis

Costanza

Musio

Abou-Hamdan

et al. 2013

The Journal of Immunology

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Predominance of multiple sclerosis (MS) in women, reductions of disease flares during pregnancy, and their increase in the postpartum period have suggested a hormonal influence on MS activity. The hormone prolactin (PRL) has long been debated as a potential immune-stimulating factor in several autoimmune disorders, including MS and its animal model experimental autoimmune encephalomyelitis (EAE). However, to date, no data clearly ascribe a pathogenic role to PRL in these diseases. Using PRL receptor–deficient (Prlr−/−) and PRL-deficient (Prl−/−) mice, we show that PRL plays a redundant role in the development of chronic EAE. In Prlr−/− and Prl−/− mice, EAE developed with a delayed onset compared with littermate control mice, but with full clinical severity. In line with the clinical outcome, T cell proliferation and production of IFN-γ, IL-17A, and IL-6 induced by myelin Ag were delayed in Prlr−/− and Prl−/− mice. Ag-specific IgG Ab responses were not affected by PRLR or PRL deficiency. We also show that mouse lymph node cells and purified CD4+ T cells express transcript for Prlr, but not for Prl. These results reveal that PRL does not play a central role in the development of chronic EAE and optimal Th1 and Th17 responses against myelin. Moreover, they also rule out a possible contribution of PRL secreted by immune cells to the modulation of autoreactive T cell response in this model.

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Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Cited by 89 publications

References 44 publications

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Prolactin Is Not Required for the Development of Severe Chronic Experimental Autoimmune Encephalomyelitis

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Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Cited by 89 publications

References 44 publications

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Dual roles of PGE 2 -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Prolactin Is Not Required for the Development of Severe Chronic Experimental Autoimmune Encephalomyelitis

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Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis