title: Non-muscle Mlck is required for β-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1β-mediated barrier dysfunction in brain endothelial cells.
abstract: Aberrant elevation in the levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) contributes to neuroinflammatory diseases. Blood-brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation. It is known that IL-1β directly induces BBB hyperpermeability but the mechanisms remain unclear. Claudin-5 (Cldn5) is a tight junction protein found at endothelial cell-cell contacts that are crucial for maintaining brain microvascular endothelial cell (BMVEC) integrity. Transcriptional regulation of Cldn5 has been attributed to the transcription factors β-catenin and forkhead box protein O1 (FoxO1), and the signaling molecules regulating their nuclear translocation. Non-muscle myosin light chain kinase (nmMlck, encoded by the Mylk gene) is a key regulator involved in endothelial hyperpermeability, and IL-1β has been shown to mediate nmMlck-dependent barrier dysfunction in epithelia. Considering these factors, we tested the hypothesis that nmMlck modulates IL-1β-mediated downregulation of Cldn5 in BMVECs in a manner that depends on transcriptional repression mediated by β-catenin and FoxO1. We found that treating BMVECs with IL-1β induced barrier dysfunction concomitantly with the nuclear translocation of β-catenin and FoxO1 and the repression of Cldn5. Most importantly, using primary BMVECs isolated from mice null for nmMlck, we identified that Cldn5 repression caused by β-catenin and FoxO1 in IL-1β-mediated barrier dysfunction was dependent on nmMlck.
authors: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
authors: Richard S
authors: RS
authors: Beard
authors: Ricci J
authors: RJ
authors: Haines
authors: Kevin Y
authors: KY
authors: Wu
authors: Jason J
authors: JJ
authors: Reynolds
authors: Stephanie M
authors: SM
authors: Davis
authors: John E
authors: JE
authors: Elliott
authors: Nikolay L
authors: NL
authors: Malinin
authors: Victor
authors: V
authors: Chatterjee
authors: Byeong J
authors: BJ
authors: Cha
authors: Mack H
authors: MH
authors: Wu
authors: Sarah Y
authors: SY
authors: Yuan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D062507:Claudin-5 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology*; D051379:Mice; D055806:Microvessels / Q000473:pathology; D009219:Myosin-Light-Chain Kinase / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D015533:Transcriptional Activation; D051176:beta Catenin / Q000502:physiology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D053583:Interleukin-1beta; D009219:Myosin-Light-Chain Kinase; D051176:beta Catenin; D000099152:Cadherin 5; C495267:CTNNB1 protein, mouse; C491511:Cldn5 protein, mouse; C467200:Foxo1 protein, mouse; C561451:non-muscle myosin light-chain kinase, mouse
keywords: Blood–brain barrier; Claudin-5; FoxO1; IL-1β; Neuroinflammation; Non-muscle myosin light chain kinase; β-catenin