| Autor: |
Wu D; Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK., Cerutti C; Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK., Lopez-Ramirez MA; 1] Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK [2] Department of Medicine, University of California, San Diego, La Jolla, California, USA., Pryce G; Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., King-Robson J; Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Simpson JE; Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK., van der Pol SM; Blood-Brain Barrier Research Group, Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands., Hirst MC; Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK., de Vries HE; Blood-Brain Barrier Research Group, Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands., Sharrack B; Department of Neurology, Sheffield Teaching Hospitals NHS Trust, University of Sheffield, Sheffield, UK., Baker D; Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Male DK; Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK., Michael GJ; Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Romero IA; Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK. |
| Abstrakt: |
Pro-inflammatory cytokine-induced activation of nuclear factor, NF-κB has an important role in leukocyte adhesion to, and subsequent migration across, brain endothelial cells (BECs), which is crucial for the development of neuroinflammatory disorders such as multiple sclerosis (MS). In contrast, microRNA-146a (miR-146a) has emerged as an anti-inflammatory molecule by inhibiting NF-κB activity in various cell types, but its effect in BECs during neuroinflammation remains to be evaluated. Here, we show that miR-146a was upregulated in microvessels of MS-active lesions and the spinal cord of mice with experimental autoimmune encephalomyelitis. In vitro, TNFα and IFNγ treatment of human cerebral microvascular endothelial cells (hCMEC/D3) led to upregulation of miR-146a. Brain endothelial overexpression of miR-146a diminished, whereas knockdown of miR-146a augmented cytokine-stimulated adhesion of T cells to hCMEC/D3 cells, nuclear translocation of NF-κB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-κB activity upon cytokine activation through targeting two novel signaling transducers, RhoA and nuclear factor of activated T cells 5, as well as molecules previously identified, IL-1 receptor-associated kinase 1, and TNF receptor-associated factor 6. We propose brain endothelial miR-146a as an endogenous NF-κB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation. |
