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

ABSTRACT: Pro-inflammatory cytokine-induced activation of nuclear factor, NF-?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-?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, TNF? and IFN? 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-?B, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-?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-?B inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation.

SUBMITTER: Wu D

PROVIDER: S-EPMC4348377 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Wu Dongsheng D Cerutti Camilla C Lopez-Ramirez Miguel A MA Pryce Gareth G King-Robson Josh J Simpson Julie E JE van der Pol Susanne Ma SM Hirst Mark C MC de Vries Helga E HE Sharrack Basil B Baker David D Male David K DK Michael Gregory J GJ Romero Ignacio A IA

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20141217 3

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 ...[more]

PMID: 25515214

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Dataset Information

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

Publications

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

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