ReviewInflammation at the blood-brain barrier: The role of liver X receptors
Section snippets
The blood-brain barrier
The blood-brain barrier (BBB) is responsible for maintaining brain homeostasis by controlling the environment of the central nervous system (CNS), the entry of nutrients, and by protecting it against xenobiotics. The physical barrier is formed by specialized endothelial cells, which have unique properties. Brain endothelial cells exhibit low pinocytotic activity and are sealed with adherens junctions (AJs) like VE-cadherin and E-cadherin that are connected to the cytoskeleton via catenins.
The BBB in neuroinflammatory diseases
In numerous pathological conditions of the CNS, including ischemic stroke, multiple sclerosis, and Alzheimer's disease, neuroinflammation contributes to the progression of clinical symptoms and may lead to neurodegeneration. Moreover, a dysfunction of the BBB is associated with these disorders. BBB dysfunction is characterized by endothelial cell junctional alterations and increased permeability. This can be induced by inflammation and vasoactive compounds in a disease-specific manner and
BBB alterations in neuroinflammation: cellular changes
The tight regulation of BBB function and its specific interactions with the environment ensures the preservation of CNS homeostasis. As mentioned, BBB dysfunction during disease can involve disruption of TJs, increase in transcytosis, changes in transport properties, and increased leukocyte infiltration, which are processes that are orchestrated by all cell types of the NVU. Their individual role in neuroinflammation is discussed below.
The liver X receptor; the missing link?
Interestingly, apart from neuroinflammation, a dysregulation of brain cholesterol homeostasis has been observed in the above-described pathological conditions. Cholesterol is a major component of cell membranes and as such it contributes to the regulation of cellular structure and function. While the brain on average only comprises 2.5% of the total body mass, it contains about 23% of the body's total cholesterol, underlining its importance in brain function (Martin et al., 2014). Almost all
Future perspectives
Activation of LXRs may be considered a promising therapeutic target in stroke, MS, and AD. LXR agonists decrease brain inflammation and exert protective effects of BBB function. Yet, there are some important points to consider before the administration of LXR agonists may become a novel therapeutic approach.
For instance, the specific roles of the individual LXRα and LXRβ subtypes are at present unknown and research focusing on LXR function in the brain rarely makes a distinction between the two
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by grants from the ZonMw Memorabel program (NMdW; project nr 733050105) and from the Dutch MS Research Foundation (AK; grant MS-09-358d).
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