Blood–brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE

Bennett, Jami; Basivireddy, Jayasree; Kollar, Anita; Biron, Kaan E.; Reickmann, Peter; Jefferies, Wilfred A.; McQuaid, Stephen

doi:10.1016/j.jneuroim.2010.08.011

Cited by 229 publications

(183 citation statements)

References 37 publications

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“…Geoffrey Paltser, 1 1,2 Yuko Maezawa, 1,2 Lindsay S Cahill, 4 Christine L Laliberté, 4 Sreeram V Ramagopalan, 5 Gabriele C DeLuca, 5 A Dessa Sadovnick,6 Igor Astsaturov, 7 George C Ebers, 5 R Mark Henkelman, 4 Michael W Salter, 1,3 and H-Michael Dosch 1,2 as largely a heat sensor, TRPV1 is emerging as a major controller of pleiotropic functions in different tissue milieus. Abnormal TRPV1 activity can alter the severity and progression of peripheral inflammatory conditions dramatically, including type 1 diabetes (T1D), colitis and arthritis, through mechanisms largely mediated by its local efferent secretory function: too little in T1D, too much in colitis and arthritis (14)(15)(16).…”

Section: Trpv1 Gates Tissue Access and Sustains Pathogenicity In Automentioning

confidence: 99%

“…Its etiology remains unclear, though tissue damage is autoimmune in nature, with several genetic disease risk loci mapped to T cell function (2)(3)(4). A key step in disease is thought to be impairment of the bloodbrain barrier (BBB), a logical, but elusive target for therapeutic intervention (5). This physical barrier is established early during embryogenesis and involves a neurovascular unit of pericytes, astrocytes, neurons, endothelial cells, and microglia (PANEM) (6).…”

Section: Introductionmentioning

confidence: 99%

“…This physical barrier is established early during embryogenesis and involves a neurovascular unit of pericytes, astrocytes, neurons, endothelial cells, and microglia (PANEM) (6). Normally, tight junctions and low vascular adhesiveness greatly inhibit extravasation into CNS tissue (5). Disruption of the BBB triggers a complex cascade of events in which the interactive PANEM tissue elements respond to secreted mediators of immune or neuronal derivation (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis

Paltser

Liu

Yantha

et al. 2013

Mol Med

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Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1 -/-B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1 + neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P . In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.

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Section: Trpv1 Gates Tissue Access and Sustains Pathogenicity In Automentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis

Paltser

Liu

Yantha

et al. 2013

Mol Med

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“…Dysfunction of the BBB and BSCB is a common feature of several neurologic conditions, including traumatic brain and spinal cord injury, stroke, neuromyelitis optica (NMO), and multiple sclerosis (MS) (3)(4)(5). In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), the BSCB is compromised, thereby exposing the fragile CNS environment to the immune system and its cellular arsenal.…”

mentioning

confidence: 99%

“…In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), the BSCB is compromised, thereby exposing the fragile CNS environment to the immune system and its cellular arsenal. This leads to immune cell invasion, formation of demyelinated lesions, and axonal damage (4,(6)(7)(8). Early breakdown of the BSCB in EAE has been widely documented, but the precise timing and triggers of this disruption are still a matter of debate (9)(10)(11)(12).…”

mentioning

confidence: 99%

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

Aubé

Lévesque

Paré

et al. 2014

The Journal of Immunology

187

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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