How do immune cells overcome the blood–brain barrier in multiple sclerosis?

Larochelle, Catherine; Alvarez, Jorge Iván; Prat, Alexandre

doi:10.1016/j.febslet.2011.04.066

Cited by 330 publications

(275 citation statements)

References 209 publications

(269 reference statements)

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“…In particular, disrupted occludin expression and distribution have been reported within the microvascular endothelium of patients with MS (27), clearly paralleling our findings in AnxA1 −/− mice and AS hCMEC/D3 clones. It is important to note that endothelial ANXA1 down-regulation occurs in normal-appearing white matter, a finding that may inform the extensive discussion whether deficits in BBB permeability precede leukocyte extravasation or are a consequence of immune cell accumulation (28). In particular, our finding that ANXA1 down-regulation occurs at sites distant from active lesions strongly suggests a preexisting weakening of BBB integrity before leukocyte extravasation and the development of active demyelination.…”

Section: Discussionmentioning

confidence: 81%

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Cristante

McArthur

Mauro

et al. 2012

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

176

218

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The blood-brain barrier (BBB), a critical guardian of communication between the periphery and the brain, is frequently compromised in neurological diseases such as multiple sclerosis (MS), resulting in the inappropriate passage of molecules and leukocytes into the brain. Here we show that the glucocorticoid anti-inflammatory messenger annexin A1 (ANXA1) is expressed in brain microvascular endothelial cells, where it regulates BBB integrity. In particular, ANXA1 −/− mice exhibit significantly increased BBB permeability as a result of disrupted interendothelial cell tight junctions, essentially related to changes in the actin cytoskeleton, which stabilizes tight and adherens junctions. This situation is reminiscent of early MS pathology, a relationship confirmed by our detection of a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of patients with MS. Importantly, this loss is swiftly restored by i.v. administration of human recombinant ANXA1. Analysis in vitro confirms that treatment of cerebrovascular endothelial cells with recombinant ANXA1 restores cell polarity, cytoskeleton integrity, and paracellular permeability through inhibition of the small G protein RhoA. We thus propose ANXA1 as a critical physiological regulator of BBB integrity and suggest it may have utility in the treatment of MS, correcting BBB function and hence ameliorating disease.T he presence of narrow and dense tight junctions between adjacent endothelial cells is peculiar to the cerebral vasculature, and their integrity is essential for the maintenance of correct blood-brain barrier (BBB) function as the primary regulator of cross-talk between the brain and the rest of the body (1). Increasing evidence indicates that the integrity of this structural and functional barrier is compromised in neurological conditions such as multiple sclerosis (MS), Alzheimer's, and Parkinson diseases, leading to the failure of the normal mechanisms controlling passage of substances into the brain (2) and to the sensitization and/or worsening of pathologic conditions. Pharmacological intervention to prevent or correct BBB alteration in such diseases is a difficult task, but potential therapeutic leads can be gained from the study of endogenous mediators regulating barrier integrity.Annexin A1 (ANXA1) is an important anti-inflammatory protein, principally known as a regulator of peripheral leukocyte migration and a promoter of macrophage phagocytosis (3). ANXA1 is expressed in several cell types within the brain, including ependyma and microglia, but in particular in the endothelium of the brain microvasculature (4), although its role in these cells remains obscure. We have previously shown glucocorticoids to up-regulate expression of ANXA1 in the cerebral endothelium (5), and, given that glucocorticoids enhance BBB tightness (6), we hypothesized that ANXA1 may play a role in the regulation of BBB permeability. Through combined in vitro and in vivo approaches, we have identified a dual role for ANXA1 in organizing the interendothelial cell...

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Section: Discussionmentioning

confidence: 81%

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Cristante

McArthur

Mauro

et al. 2012

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

176

218

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“…The results of our study corroborate other findings where exercise produced an immunomodulatory effect, by reducing the pro-inflammatory and increasing the anti-inflammatory cytokines (Souza et al 2016). Production of TNF-α directly affects the BBB permeability (Larochelle et al 2011). Evidence has shown that physical exercise inhibited the production of pro-inflammatory cytokines, upregulated the regulatory T cells, and suppressed IL-6 and TNF-α production associated with the inhibition of adhesion molecules and reestablishment of tight junction protein expression, thereby restraining BBB permeability (Mota et al 2012, Souza et al 2016.…”

Section: Discussionmentioning

confidence: 99%

Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women

Chupel

Minuzzi

Furtado

et al. 2018

Appl. Physiol. Nutr. Metab.

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1Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women Authors:Matheus Abstract:Immunosenescence contribute to increase the blood-brain barrier (BBB) permeability, leading cognitive impairment and neurodegeneration. Thus, we investigated the anti-inflammatory effect of exercise and taurine supplementation on peripheral markers of blood-brain barrier, inflammation, and cognition of elderly women. Forty-eight elderly women (83.58±6.9 years) participated in the study, and were allocated into combined exercise training (CET: n=13), taurine supplementation (TAU: n=12), exercise training associated with taurine (CET+TAU: n=11), or control group (CG: n=12). Exercise was applied twice a week (multi-modal exercise). Taurine ingestion was 1.5g., once a day. Participants were evaluated before and after 14-weeks of intervention. Plasma levels of IL-1β, IL-1ra, IL-6, IL-10, IL-17, TNF-α, and serum concentration of S100β and neuron specific enolase (NSE) were determined. The mini mental state examination (MMSE) was also applied.Concentrations of S100β were maintained in all intervention groups, while a subtle increase in the CG was found. NSE levels increased only in TAU group (p<0.05). CET reduced TNF-α, IL-6, and IL-1β/IL-1ra, IL-6/IL10, TNF-α/IL-10 ratios (p<0.05). TAU decreased the IL-1β/IL-1ra ratio (p<0.05). MMSE score increased only in CET+TAU group (p<0.05). Multiple regression analysisshowed that there was a trend for changes in IL-1β and CCI to be independently associated with changes in S100β. Exercise and taurine decreased inflammation, and maintained the BBB integrity in elderly women. Exercise emerged as an important tool to improve brain health even when started at advanced ages.

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“…B cells are also essential in MS immunopathogenesis, as antibodies produced within the CNS are a fundamental feature of the disease (i.e., oligoclonal bands) and as B-cell-directed therapies provide strong protection against lesion formation. It is clear that during immune cell infiltration and lesion formation, BBB function becomes compromised (Larochelle et al 2011), which is characterized by vascular leakage associated with alterations of junctional proteins. Analysis of MS tissue shows that abnormalities in the expression of junctional proteins coincide with perivascular astrogliosis, and such changes are detected in very early stages of lesion formation ).…”

Section: Ms and Related Disordersmentioning

confidence: 99%

The Blood–Brain Barrier

Daneman

Prat

2015

Cold Spring Harb Perspect Biol

Self Cite

2,548

1,829

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Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.

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How do immune cells overcome the blood–brain barrier in multiple sclerosis?

Cited by 330 publications

References 209 publications

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women

The Blood–Brain Barrier

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