Review
The blood–brain barrier and immune function and dysfunction

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Abstract

The blood–brain barrier (BBB) is the monocellular interface that divides the peripheral circulation from direct contact with the central nervous system (CNS). This interface consists of several parallel barriers that include most notably the capillary bed of the CNS and the choroid plexus. These barriers at one level create the dichotomy between the circulating factors of the immune system and the components of the CNS only to regulate interactions between the immune and central nervous systems at other levels. The BBB is thus an integral part of the neuroimmune axis. Here, we will consider four aspects of BBB–neuroimmune interactions: BBB disruption as mediated by LPS and cytokines, cytokine transport across the BBB, immune cell trafficking, and effects of lipopolysaccharide (LPS) on various functions of the BBB.

Introduction

Interactions between the immune system and the central nervous system (CNS) are increasingly recognized. The mechanisms by which the immune system and CNS interact are numerous, but share a common conceptual theme of the transfer of information from one system to the other. Two broad categories of the mechanisms of interaction are nervous transmission and humoral transmission. Afferent and efferent nerves, exemplified by the vagus, form a neuroimmune link between the CNS with peripheral tissues as diverse as the gastrointestinal tract, spleen, and soft palate. Humoral transmission relies on the blood stream to deliver products of the peripheral immune system to the brain and to convey secretions of the brain to elements of the peripheral immune system. However, the circulation through the brain differs from that of most peripheral tissues in that the capillary bed of the brain does not produce an ultrafiltrate (Reese and Karnovsky, 1967, Broman, 1950). This lack of leakage is a main basis underlying the concept of the blood–brain barrier (BBB). This review will concentrate on the role the BBB plays in both separating and conjoining the immune and central nervous systems. It will focus on 4 aspects of BBB–neuroimmune interactions: BBB disruption, cytokine transport across the BBB, immune cell trafficking, and effects of lipopolysaccharide (LPS) on the BBB.

Section snippets

Relevant concepts of the BBB

The BBB can be conceptualized as those mechanisms that control the exchange of substances between the blood and the fluids of the brain. The concept of the BBB arose from studies in the late 19th century that found that basic dyes injected into the blood did not stain the brain and that bile acids produced seizures when directly injected into the brain but not when injected peripherally (Davson, 1967). The dyes and bile acids were prevented from entering the brain because they bound tightly to

Neuroimmune interactions with the BBB

Nearly every category of BBB function is involved with the neuroimmune system. Table 2 lists some examples of these interactions and is by no means exhaustive. As detailed below, these interactions between the BBB and the neuroimmune system are likely involved in physiologic regulation, in adaptions to stress, and in disease processes. Currently, much more is known about how the BBB is involved in or responds to the neuroimmune system than about the consequences of those responses. The rest of

Disruption of the BBB

Early work showed that LPS can disrupt the BBB (Wispelwey et al., 1988). Subsequent studies showed that tumor necrosis factor-alpha (TNF) could mediate some of these actions and likely did so by processes that involved cytoskeletal rearrangement (Quagliarello et al., 1991, Deli et al., 1995). Early work with interleukin-2 (IL-2) suggested it also disrupted the BBB (Ellison et al., 1987), but subsequent work could not replicate this effect of IL-2 (Banks and Kastin, 1992) and suggested that

Cytokine transport across the BBB

Numerous cytokines have been found to be transported across the BBB by saturable transport systems (Banks, 2005, Pan and Kastin, 2008). The BBB has cytokine binding sites that alter intracellular function (receptors) or convey the cytokine across the BBB (transporters). In some cases, the transporter seems to be a product of the same gene encoding for the cytokine receptor involved in activating intracellular machinery. For example, both the p75 and p55 receptor for tumor necrosis factor-alpha

Immune cell trafficking

Passage of immune cells across the BBB depends upon an elaborate interaction between the immune cell and the BBB termed diapedesis. Most studies have not been in normal animals but in models of multiple sclerosis (MS). The most commonly used animal models in the study of MS are those of experimental autoimmune encephalomyelitis (EAE,) which is induced by generating a T-cell-mediated autoimmune response against CNS antigen (Lassmann, 2008). Origins of this model date back to the late 1800s, when

LPS actions at the BBB

LPS has numerous effects on the BBB. Originally, LPS was noted to disrupt the BBB (Wispelwey et al., 1988). Since then LPS has been noted to affect BBB permeability in other ways. It increases absorptive endocytosis, a process that depends on interactions of glycoproteins on the surface of the cell composing the BBB with glycoproteins of the transported moiety (Banks et al., 1999). The human immunodeficiency virus and its surface coat glycoprotein gp120 can enter the brain by this mechanism and

Conclusions

The BBB is intimately involved with the neuroimmune system. Indeed, its physical location divides and so defines these two compartments. Pathological disruption of the BBB by LPS and cytokines was the first clear interaction between the neuroimmune system and the BBB. Other interactions include immune cell trafficking, transport of cytokines, modulation of BBB saturable transport systems and other mechanisms of permeation, and secretion of neuroimmune substances by the BBB. These mechanisms of

References (112)

  • GrossP.M. et al.

    The microcirculation of rat circumventricular organs and the pituitary gland

    Brain Res. Bull.

    (1987)
  • HofmanF. et al.

    HIV-tat protein induces the production of interleukin-8 by human brain-derived endothelial cells

    J. Neuroimmunol.

    (1999)
  • HurwitzA.A. et al.

    The role of the blood–brain barrier in HIV infection of the central nervous system

    Adv. Neuroimmunol.

    (1994)
  • JaegerL.B. et al.

    Effects of lipopolysaccharide on the blood–brain barrier transport of amyloid bea protein: a mechanism for inflammation in the progression of Alzheimer's disease

    Brain Behav Immun

    (2009)
  • KobilerD. et al.

    Sodium dodecylsulphate induces a breach in the blood–brain barrier and enables a West Nile virus variant to penetrate into mouse brain

    Brain Res.

    (1989)
  • LeeY.W. et al.

    Cocaine activates redox-regulated transcription factors and induces TNF-alpha expression in human brain endothelial cells

    Brain Res.

    (2001)
  • LiA. et al.

    Dysfunction of splenic macrophages in cirrhotic patients with hypersplenism and HBV infection

    Am. J. Med. Sci.

    (2008)
  • LiuH.C. et al.

    Dual effects of morphine on permeability and apoptosis of vascular endothelial cells: morphine potentiates lipopolysaccharide-induced permeability and apoptosis of vascular endothelial cells

    J. Neuroimmunol.

    (2004)
  • MCGuireT.R. et al.

    Release of prostaglandin E-2 in bovine brain endothelial cells after exposure to three unique forms of the antifungal drug amphotericin-B: role of COX-2 in amphotericin-B induced fever

    Life Sci.

    (2003)
  • MinamiT. et al.

    Penetration of cisplatin into mouse brain by lipopolysccharide

    Toxicology

    (1998)
  • NeuweltE. et al.

    Strategies to advance translational research into brain barriers

    Lancet Neurol.

    (2008)
  • OsmersI. et al.

    PSGL-1 is not required for development of experimental autoimmune encephalomyelitis

    J. Neuroimmunol.

    (2005)
  • OztasB. et al.

    Sex-dependent changes in blood–brain barrier permeability in epileptic rats following acute hyperosmotic exposure

    Pharmacol. Res.

    (2001)
  • PanW. et al.

    Entry of EGF into brain is rapid and saturable

    Peptides

    (1999)
  • PanW. et al.

    TNFα transport across the blood–brain barrier is abolished in receptor knockout mice

    Exp. Neurol.

    (2002)
  • PuH. et al.

    HIV-1 Tat protein upregulates inflammatory mediators and induces monocyte invasion into the brain

    Mol. Cell. Neurosci.

    (2003)
  • QuanN. et al.

    Brain-immune communication pathways

    Brain Behav. Immun.

    (2007)
  • ReyesT.M. et al.

    Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli

    Brain Res.

    (1999)
  • RomeoH.E. et al.

    The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity

    J. Neuroimmunol.

    (2001)
  • SimpsonJ.E. et al.

    Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis

    J. Neuroimmunol.

    (1998)
  • StuveO.

    The effects of natalizumab on the innate and adaptive immune system in the central nervous system

    J. Neurol. Sci.

    (2008)
  • AncutaP. et al.

    Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients

    PLoS ONE

    (2008)
  • AndrasI.E. et al.

    HIV-1 Tat protein alters tight junction protein expression and distribution in cultured brain endothelial cells

    J. Neurosci. Res.

    (2003)
  • AvisonM.J. et al.

    Inflammatory changes and breakdown of microvascular integrity in early human immunodeficiency virus dementia

    J. Neurovirol.

    (2004)
  • BanksW.A.

    Blood–brain barrier transport of cytokines: a mechanism for neuropathology

    Curr. Pharm. Des.

    (2005)
  • BanksW.A.

    Editorial: the blood–brain barrier as a cause of disease

    Curr. Pharm. Des.

    (2008)
  • BanksW.A. et al.

    Human interleukin (IL) 1α, murine IL-1α and murine IL-1β are transported from blood to brain in the mouse by a shared saturable mechanism

    J. Pharmacol. Exp. Ther.

    (1991)
  • BanksW.A. et al.

    Passage of cytokines across the blood–brain barrier

    Neuroimmunomodulation

    (1995)
  • BanksW.A. et al.

    Intravenous human interleukin-1α impairs memory processing in mice: dependence on blood–brain barrier transport into posterior division of the septum

    J. Pharmacol. Exp. Ther.

    (2001)
  • BanksW.A. et al.

    Nitric oxide isoenzymes regulate LPS-enhanced insulin transport across the blood–brain barrier

    Endocrinology

    (2008)
  • BauerB. et al.

    Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood–brain barrier

    Mol. Pharmacol.

    (2007)
  • BaxterA.G.

    The origin and application of experimental autoimmune encephalomyelitis

    Nat. Rev. Immunol.

    (2007)
  • BegleyD.J.

    ABC transporters and the blood–brain barrier

    Curr. Pharm. Des.

    (2004)
  • BovenL.A. et al.

    Monocytes infiltration is highly associated with loss of tight junction protein zonula occludens in HIV-1-associated dementia

    Neuropathol. Appl. Neurobiol.

    (2000)
  • BrenchleyJ.M. et al.

    Microbial translocation is a cause of systemic immune activation in chronic HIV injection

    Nat. Med.

    (2006)
  • BromanT.

    Supravital analysis of disorders in the cerebrovascular permeability

    Acta Psychiatr.

    (1950)
  • BuhlerL.A. et al.

    Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis

    BMC Neurosci.

    (2009)
  • Candelario-JalilE. et al.

    Cyclooxygenase inhibition limits blood–brain barrier disruption following intracerebral injection of tumor necrosis factor-a in the rat

    J. Pharmacol. Exp. Ther.

    (2007)
  • CaoC. et al.

    Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA by LPS in the rat brain

    Am. J. Physiol.

    (1997)
  • ChiO.Z. et al.

    Effects of 17beta-estradiol on blood–brain barrier disruption during focal ischemia in rats

    Horm. Met. Res.

    (2003)
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