Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation

Dongsheng Wu; Camilla Cerutti; Miguel A Lopez-Ramirez; Gareth Pryce; Josh King-Robson; Julie E Simpson; Susanne Ma van der Pol; Mark C Hirst; Helga E de Vries; Basil Sharrack; David Baker; David K Male; Gregory J Michael; Ignacio A Romero

doi:10.1038/jcbfm.2014.207

Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κかっぱB activation

J Cereb Blood Flow Metab. 2015 Mar;35(3):412-23. doi: 10.1038/jcbfm.2014.207. Epub 2014 Dec 17.

Affiliations

¹ Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK.
² 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.
³ Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁴ Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
⁵ Blood-Brain Barrier Research Group, Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
⁶ Department of Neurology, Sheffield Teaching Hospitals NHS Trust, University of Sheffield, Sheffield, UK.

Abstract

Pro-inflammatory cytokine-induced activation of nuclear factor, NF-κかっぱB 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-κかっぱB 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あるふぁ and IFNγがんま 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-κかっぱB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-κかっぱB 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-κかっぱB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Cell Adhesion / genetics
Encephalomyelitis, Autoimmune, Experimental / genetics*
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / metabolism
Endothelial Cells / metabolism*
Female
Humans
Immunohistochemistry
In Situ Hybridization
Inflammation
Laser Capture Microdissection
Male
Mice
MicroRNAs / metabolism*
Middle Aged
Multiple Sclerosis / genetics*
Multiple Sclerosis / immunology
Multiple Sclerosis / metabolism
NF-kappa B / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes / cytology*
T-Lymphocytes / immunology
Transfection

Substances

MIRN146 microRNA, human
MicroRNAs
Mirn146 microRNA, mouse
NF-kappa B