Please use this identifier to cite or link to this item:
http://hdl.handle.net/1942/29080
Title: | Liver X Receptor Alpha Is Important in Maintaining Blood-Brain Barrier Function | Authors: | WOUTERS, Elien de Wit, Nienke M. VANMOL, Jasmine van der Pol, Susanne M. A. Hof, Bert van Het SOMMER, Daniela LOIX, Melanie Geerts, Dirk Gustafsson, Jan Ake Steffensen, Knut R. VANMIERLO, Tim BOGIE, Jeroen HENDRIKS, Jerome de Vries, Helga E. |
Issue Date: | 2019 | Publisher: | FRONTIERS MEDIA SA | Source: | FRONTIERS IN IMMUNOLOGY, 10 (Art N° 1811) | Abstract: | Dysfunction of the blood-brain barrier (BBB) contributes significantly to the pathogenesis of several neuroinflammatory diseases, including multiple sclerosis (MS). Potential players that regulate BBB function are the liver X receptors (LXRs), which are ligand activated transcription factors comprising two isoforms, LXR alpha, and LXR beta. However, the role of LXR alpha, and LXR beta in regulating BBB (dys)function during neuroinflammation remains unclear, as well as their individual involvement. Therefore, the goal of the present study is to unravel whether LXR isoforms have different roles in regulating BBB function under neuroinflammatory conditions. We demonstrate that LXR alpha, and not LXR beta, is essential to maintain barrier integrity in vitro. Specific knockout of LXR alpha in brain endothelial cells resulted in a more permeable barrier with reduced expression of tight junctions. Additionally, the observed dysfunction was accompanied by increased endothelial inflammation, as detected by enhanced expression of vascular cell adhesion molecule (VCAM-1) and increased transendothelial migration of monocytes toward inflammatory stimuli. To unravel the importance of LXR alpha in BBB function in vivo, we made use of the experimental autoimmune encephalomyelitis (EAE) MS mouse model. Induction of EAE in a constitutive LXR alpha knockout mouse and in an endothelial specific LXR alpha knockout mouse resulted in a more severe disease score in these animals. This was accompanied by higher numbers of infiltrating leukocytes, increased endothelial VCAM-1 expression, and decreased expression of the tight junction molecule claudin-5. Together, this study reveals that LXR alpha is indispensable for maintaining BBB integrity and its immune quiescence. Targeting the LXR alpha isoform may help in the development of novel therapeutic strategies to prevent BBB dysfunction, and thereby neuroinflammatory disorders. | Notes: | [Wouters, Elien; Vanmol, Jasmine; Sommer, Daniela; Loix, Melanie; Vanmierlo, Tim; Bogie, Jeroen F. J.; Hendriks, Jerome J. A.] Hasselt Univ, Biomed Res Inst, Sch Life Sci, Diepenbeek, Belgium. [de Wit, Nienke M.; van der Pol, Susanne M. A.; Hof, Bert van Het; de Vries, Helga E.] Vrije Univ Amsterdam, Dept Mol Cell Biol & Immunol, Amsterdam Neurosci, MS Ctr Amsterdam,Amsterdam UMC, Amsterdam, Netherlands. [Geerts, Dirk] Univ Amsterdam, Dept Med Biol, Amsterdam UMC, Amsterdam, Netherlands. [Gustafsson, Jan Ake] Univ Houston, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA. [Gustafsson, Jan Ake; Steffensen, Knut R.] Karolinska Inst, Div Clin Chem, Dept Lab Med, Stockholm, Sweden. [Vanmierlo, Tim] Maastricht Univ, Sch Mental Hlth & Neurosci, Div Translat Neurosci, Maastricht, Netherlands. | Keywords: | blood-brain barrier; permeability; endothelium; liver X receptors; neuroinflammation;blood-brain barrier; permeability; endothelium; liver X receptors; neuroinflammation | Document URI: | http://hdl.handle.net/1942/29080 | ISSN: | 1664-3224 | e-ISSN: | 1664-3224 | DOI: | 10.3389/fimmu.2019.01811 | ISI #: | 000477995600001 | Rights: | 2019 Wouters, de Wit, Vanmol, van der Pol, van het Hof, Sommer, Loix, Geerts, Gustafsson, Steffensen, Vanmierlo, Bogie, Hendriks and de Vries. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2020 |
Appears in Collections: | Research publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
wouters 1.pdf | Published version | 1.97 MB | Adobe PDF | View/Open |
SCOPUSTM
Citations
3
checked on Sep 7, 2020
WEB OF SCIENCETM
Citations
28
checked on Oct 14, 2024
Page view(s)
136
checked on Sep 7, 2022
Download(s)
148
checked on Sep 7, 2022
Google ScholarTM
Check
Altmetric
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.