Trends in Parasitology
Volume 28, Issue 8, August 2012, Pages 311-319
Journal home page for Trends in Parasitology

Review
The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes

https://doi.org/10.1016/j.pt.2012.05.008Get rights and content

Homeostasis implies constant operational defence mechanisms, against both external and internal threats. Infectious agents are prominent among such threats. During infection, the host elicits the release of a vast array of molecules and numerous cell–cell interactions are triggered. These pleiomorphic mediators and cellular effects are of prime importance in the defence of the host, both in the systemic circulation and at sites of tissue injury, for example, the blood–brain barrier (BBB). Here, we focus on the interactions between the endothelium, astrocytes, and the molecules they release. Our review addresses these interactions during infectious neurological diseases of various origins, especially cerebral malaria (CM). Two novel elements of the interplay between endothelium and astrocytes, microparticles and the kynurenine pathway, will also be discussed.

Section snippets

Blood–brain barrier (BBB) overview: a crucial interface

The existence of the BBB was first described in 1885 by Ehrlich, when he showed that after systemic injection of a dye into the blood circulation, the parenchyma of the brain remained unstained. More recently, this multicellular anatomical system was referred to as a neurovascular unit [1], extending its definition from an anatomical barrier to a functional unit where the cells that compose it display specific crosstalk and homeostatic signalling between them. The BBB or neurovascular unit is

Endothelial cells in infections

A wide range of infectious diseases are associated with BBB disturbances [8]. Pathogens interact with brain ECs via several ligand proteins that have been characterised, as have been the EC surface receptors (reviewed in [9]). Among pattern recognition receptors, selected sets of Toll-like receptors (TLRs) are used by pathogens [10]. A remarkable review of neuroinfections, with a historical perspective, has been published recently [11].

Pathogens can either affect brain ECs by infecting them

Astrocytes and infection

Very much like the other major cell of the BBB, the EC, the astrocytes can be both targeted or directly infected by several pathogens [7]. Astrocytes have the ability to recognise structures belonging to various types of pathogens. Notably, they express low levels of mannan binding lectin, a defence collagen, primarily released by phagocytes but also by astrocyte cell lines that can recognise bacterial or fungal wall molecules (pathogen-associated molecular patterns, PAMPs) and can selectively

Endothelial–astrocyte interplay

Complex endothelial–astrocyte interactions and particularly astroglial–endothelial signalling are essential for BBB integrity in homeostasis and pathological conditions (reviewed in [40]). EC permeability, among many functions, is affected by soluble factors from astrocytes. Direct evidence of interplay has been provided by the demonstration that astrocyte-conditioned medium stimulates human brain ECs to increase their expression of the tight junction protein zona occludens (ZO)-1, resulting in

Post-infectious complications of CM

Can a unifying hypothesis for the involvement of immunopathological and ischaemic mechanisms be proposed? Two distinct, and thus far separately investigated, mechanisms are thought to be important in the pathogenesis of a major neuroinflammatory disease, CM. This hypothesis could be extended to other pathologies with similar features: ischaemia due to microvascular obstruction and immunopathological reactions. How might these two theories intersect? The activities of neurons, ECs, microglia,

Concluding remarks

In stroke, obstruction of a vessel causes loss of oxygen and glucose delivery to the tissue it supplied. In the core of the ischaemic region, where the supply deficit is most severe, astrocytes and neurons perish through a network of interrelated processes, many of which are due to severe loss of intracellular ATP [68]. Surrounding this core is the hypoperfused penumbral region, in which cellular ATP is less compromised. It is now believed that astrocytes hold the key to whether neurons regain

Acknowledgement

The study was funded by the National Health and Medical Research Council of Australia (Project Grants #1009914 to GJG, VC and GEG; #1028241 to VC and GEG and #1022368 to NHH, TLC and GEG).

Glossary

Abluminal surface
surface of the endothelium facing the basement membrane, that is, opposite their luminal surface in contact with the circulating blood.
Astrocytes
are the most abundant cells in the human central nervous system (CNS), the only organ where they are found. They are glial cells and are also known as astroglia. These represent a major component of the blood–brain barrier (BBB) and have foot processes that are in direct contact with the endothelial cells (ECs).
Astrogliosis
abnormal

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