Trends in Parasitology
ReviewThe crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes
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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2020, Brain Research BulletinCitation Excerpt :Activated microglial cells may produce pro- inflammatory mediators e.g. cytokines, free radicals etc. Further, these inflammatory mediators induce chemokines and adhesion molecules, recruit immune cells and activate other glial cells (Combes et al., 2012). Activated microglia could exert cytotoxic effects through to the release of ROS and pro-inflammatory mediators.
Blood–Brain Barrier in Cerebral Malaria: Pathogenesis and Therapeutic Intervention
2019, Trends in ParasitologyCitation Excerpt :The loss of ensheathed vessels might contribute to the disruption of the BBB (Figure 4). Combes et al. [64] proposed that astrocytes could be the potential convergence point of the two major proposed mechanisms of CM pathogenesis, that is, the cytokine response and the resulting cerebral hypoxia. During ECM, astrocytes are a source of CXCL9 (Miu et al. [65]), the chemoattractant which recruits the pathogenic T cells to the brain.
Interplay of extracellular vesicles and other players in cerebral malaria pathogenesis
2019, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :For example, the same behavioural changes, histopathological features, retinal abnormalities, and alterations to blood-brain barrier function have been detected in paediatric, adult and experimental CM [16]. The pathogenic role of various host- and pathogen-derived extracellular vesicles (EV) also has been demonstrated through the use of in vivo and in vitro models of CM [19–21]. Compatible findings also have been made in the human disease.
Astrogliopathology in the infectious insults of the brain
2019, Neuroscience LettersCitation Excerpt :In the CVOs, the blood-brain interface is formed by a rich capillary plexus harbouring a fenestrated endothelium [20] and lacking tight junction complexes in the endothelial cells [92]. Infectious agents cross the BBB in several ways (including paracellular route, transcytosis, receptor hijacking or infected leukocytes, the Trojan horse route [21,49]) after entering brain parenchyma are met by astroglial cells. Astrocytes express several receptors for pathogen-associated molecular patterns, and can possibly recognise various bacterial agents.
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Co-first authors.