Notch signaling is impaired during inflammation in a Lunatic Fringe-dependent manner

Claudio Derada Troletti, Melissa A. Lopes Pinheiro, Marc Charabati, Elizabeth Gowing, Bert van het Hof, Susanne M.A. van der Pol, Dirk Geerts, Alexandre Prat, Ruud D. Fontijn, Wendy W. Unger, Helga E. de Vries

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The blood-brain barrier (BBB) assures brain homeostasis through the specialized function of brain endothelial cells (BECs). Dysfunction of the BBB due to inflammatory processes is associated with several neurological disorders, including multiple sclerosis (MS). Understanding the mechanisms that underlie these processes may ultimately lead to new therapeutic strategies to restore BBB function, thereby fighting disease progression. In this study, we demonstrate for the first time a critical role of the Notch signaling pathway in the function of the BBB under resting and inflammatory conditions. Inhibition of the Notch signaling, either by a γ-secretase inhibitor or by genetic ablation of endothelial NOTCH, led to BBB dysfunction in vitro as evidenced by reduced transendothelial electrical resistance (TEER), altered localization and loss of endothelial junction molecules and enhanced macromolecular permeability. Inflamed BECs showed impaired Notch signaling as indicated by reduced level of the downstream targets HES-1 and HES-5. Notably, barrier function was further reduced when the Notch signaling was inhibited under inflammatory conditions, suggesting an additive effect of the Notch signaling and inflammation in BECs. In contrast, inducible overexpression of Notch-intracellular domain 1 (NICD1) rescued the detrimental effect caused by inflammation. Furthermore, we provide evidence that inflammation reduced the expression of the glycosyltransferase Lunatic Fringe (LFNG), a known positive regulator of Notch glycosylation and signaling, thereby leading to disrupted barrier function of BECs. Together, our data demonstrate the functional importance of the conserved Notch signaling pathway in control of the brain endothelial barrier and shed light on the role of LFNG in the regulation of Notch glycosylation and signaling in the adult brain vasculature in both health and disease.

Original languageEnglish
Pages (from-to)48-56
Number of pages9
JournalBrain, Behavior, and Immunity
Volume69
DOIs
Publication statusPublished - 1 Mar 2018

Cite this

Derada Troletti, Claudio ; Lopes Pinheiro, Melissa A. ; Charabati, Marc ; Gowing, Elizabeth ; van het Hof, Bert ; van der Pol, Susanne M.A. ; Geerts, Dirk ; Prat, Alexandre ; Fontijn, Ruud D. ; Unger, Wendy W. ; de Vries, Helga E. / Notch signaling is impaired during inflammation in a Lunatic Fringe-dependent manner. In: Brain, Behavior, and Immunity. 2018 ; Vol. 69. pp. 48-56.
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title = "Notch signaling is impaired during inflammation in a Lunatic Fringe-dependent manner",
abstract = "The blood-brain barrier (BBB) assures brain homeostasis through the specialized function of brain endothelial cells (BECs). Dysfunction of the BBB due to inflammatory processes is associated with several neurological disorders, including multiple sclerosis (MS). Understanding the mechanisms that underlie these processes may ultimately lead to new therapeutic strategies to restore BBB function, thereby fighting disease progression. In this study, we demonstrate for the first time a critical role of the Notch signaling pathway in the function of the BBB under resting and inflammatory conditions. Inhibition of the Notch signaling, either by a γ-secretase inhibitor or by genetic ablation of endothelial NOTCH, led to BBB dysfunction in vitro as evidenced by reduced transendothelial electrical resistance (TEER), altered localization and loss of endothelial junction molecules and enhanced macromolecular permeability. Inflamed BECs showed impaired Notch signaling as indicated by reduced level of the downstream targets HES-1 and HES-5. Notably, barrier function was further reduced when the Notch signaling was inhibited under inflammatory conditions, suggesting an additive effect of the Notch signaling and inflammation in BECs. In contrast, inducible overexpression of Notch-intracellular domain 1 (NICD1) rescued the detrimental effect caused by inflammation. Furthermore, we provide evidence that inflammation reduced the expression of the glycosyltransferase Lunatic Fringe (LFNG), a known positive regulator of Notch glycosylation and signaling, thereby leading to disrupted barrier function of BECs. Together, our data demonstrate the functional importance of the conserved Notch signaling pathway in control of the brain endothelial barrier and shed light on the role of LFNG in the regulation of Notch glycosylation and signaling in the adult brain vasculature in both health and disease.",
keywords = "Glycosylation, Inflammation, Notch signaling, Vasculature",
author = "{Derada Troletti}, Claudio and {Lopes Pinheiro}, {Melissa A.} and Marc Charabati and Elizabeth Gowing and {van het Hof}, Bert and {van der Pol}, {Susanne M.A.} and Dirk Geerts and Alexandre Prat and Fontijn, {Ruud D.} and Unger, {Wendy W.} and {de Vries}, {Helga E.}",
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language = "English",
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Notch signaling is impaired during inflammation in a Lunatic Fringe-dependent manner. / Derada Troletti, Claudio; Lopes Pinheiro, Melissa A.; Charabati, Marc; Gowing, Elizabeth; van het Hof, Bert; van der Pol, Susanne M.A.; Geerts, Dirk; Prat, Alexandre; Fontijn, Ruud D.; Unger, Wendy W.; de Vries, Helga E.

In: Brain, Behavior, and Immunity, Vol. 69, 01.03.2018, p. 48-56.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Notch signaling is impaired during inflammation in a Lunatic Fringe-dependent manner

AU - Derada Troletti, Claudio

AU - Lopes Pinheiro, Melissa A.

AU - Charabati, Marc

AU - Gowing, Elizabeth

AU - van het Hof, Bert

AU - van der Pol, Susanne M.A.

AU - Geerts, Dirk

AU - Prat, Alexandre

AU - Fontijn, Ruud D.

AU - Unger, Wendy W.

AU - de Vries, Helga E.

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N2 - The blood-brain barrier (BBB) assures brain homeostasis through the specialized function of brain endothelial cells (BECs). Dysfunction of the BBB due to inflammatory processes is associated with several neurological disorders, including multiple sclerosis (MS). Understanding the mechanisms that underlie these processes may ultimately lead to new therapeutic strategies to restore BBB function, thereby fighting disease progression. In this study, we demonstrate for the first time a critical role of the Notch signaling pathway in the function of the BBB under resting and inflammatory conditions. Inhibition of the Notch signaling, either by a γ-secretase inhibitor or by genetic ablation of endothelial NOTCH, led to BBB dysfunction in vitro as evidenced by reduced transendothelial electrical resistance (TEER), altered localization and loss of endothelial junction molecules and enhanced macromolecular permeability. Inflamed BECs showed impaired Notch signaling as indicated by reduced level of the downstream targets HES-1 and HES-5. Notably, barrier function was further reduced when the Notch signaling was inhibited under inflammatory conditions, suggesting an additive effect of the Notch signaling and inflammation in BECs. In contrast, inducible overexpression of Notch-intracellular domain 1 (NICD1) rescued the detrimental effect caused by inflammation. Furthermore, we provide evidence that inflammation reduced the expression of the glycosyltransferase Lunatic Fringe (LFNG), a known positive regulator of Notch glycosylation and signaling, thereby leading to disrupted barrier function of BECs. Together, our data demonstrate the functional importance of the conserved Notch signaling pathway in control of the brain endothelial barrier and shed light on the role of LFNG in the regulation of Notch glycosylation and signaling in the adult brain vasculature in both health and disease.

AB - The blood-brain barrier (BBB) assures brain homeostasis through the specialized function of brain endothelial cells (BECs). Dysfunction of the BBB due to inflammatory processes is associated with several neurological disorders, including multiple sclerosis (MS). Understanding the mechanisms that underlie these processes may ultimately lead to new therapeutic strategies to restore BBB function, thereby fighting disease progression. In this study, we demonstrate for the first time a critical role of the Notch signaling pathway in the function of the BBB under resting and inflammatory conditions. Inhibition of the Notch signaling, either by a γ-secretase inhibitor or by genetic ablation of endothelial NOTCH, led to BBB dysfunction in vitro as evidenced by reduced transendothelial electrical resistance (TEER), altered localization and loss of endothelial junction molecules and enhanced macromolecular permeability. Inflamed BECs showed impaired Notch signaling as indicated by reduced level of the downstream targets HES-1 and HES-5. Notably, barrier function was further reduced when the Notch signaling was inhibited under inflammatory conditions, suggesting an additive effect of the Notch signaling and inflammation in BECs. In contrast, inducible overexpression of Notch-intracellular domain 1 (NICD1) rescued the detrimental effect caused by inflammation. Furthermore, we provide evidence that inflammation reduced the expression of the glycosyltransferase Lunatic Fringe (LFNG), a known positive regulator of Notch glycosylation and signaling, thereby leading to disrupted barrier function of BECs. Together, our data demonstrate the functional importance of the conserved Notch signaling pathway in control of the brain endothelial barrier and shed light on the role of LFNG in the regulation of Notch glycosylation and signaling in the adult brain vasculature in both health and disease.

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