title: Astrocyte-derived retinoic acid: a novel regulator of blood-brain barrier function in multiple sclerosis.
abstract: Multiple sclerosis (MS) lesions are characterized by the presence of activated astrocytes, which are thought to actively take part in propagating lesion progression by secreting pro-inflammatory mediators. Conversely, reactive astrocytes may exert disease-dampening effects through the production of trophic factors and anti-inflammatory mediators. Astrocytic control of the blood-brain barrier (BBB) is crucial for normal brain homeostasis and BBB disruption is a well-established early event in MS lesion development. Here, we set out to unravel potential protective effects of reactive astrocytes on BBB function under neuroinflammatory conditions as seen in MS, where we focus on the role of the brain morphogen retinoic acid (RA). Immunohistochemical analysis revealed that retinaldehyde dehydrogenase 2 (RALDH2), a key enzyme for RA synthesis, is highly expressed by reactive astrocytes throughout white matter lesions compared to control and normal appearing white matter. In vitro modeling of reactive astrocytes resulted in increased expression of RALDH2, enhanced RA synthesis, and a protective role for astrocyte-derived RA on BBB function during inflammation-induced barrier loss. Furthermore, RA induces endothelial immune quiescence and decreases monocyte adhesion under inflammatory conditions. Finally, we demonstrated that RA attenuated oxidative stress in inflamed endothelial cells, through activation of the antioxidant transcription factor nuclear factor E2 related factor 2. In summary, RA synthesis by reactive astrocytes represents an endogenous protective response to neuroinflammation, possibly aimed at protecting the BBB against inflammatory insult. A better understanding of RA signaling in MS pathophysiology may lead to the discovery of novel targets to halt disease progression.
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands, m.mizee@vumc.nl.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Mizee
authors.forename: Philip G
authors.initials: PG
authors.lastname: Nijland
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: van der Pol
authors.forename: Joost A R
authors.initials: JA
authors.lastname: Drexhage
authors.forename: Bert
authors.initials: B
authors.lastname: van Het Hof
authors.forename: Reina
authors.initials: R
authors.lastname: Mebius
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001344:Autopsy; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase