Wednesday, 31 December 2014

Blocking white blood cell trafficking into the brain

Wu D, Cerutti C, Lopez-Ramirez MA, Pryce G, King-Robson J, Simpson JE, van der Pol SM, Hirst MC, de Vries HE, Sharrack B, Baker D, Male DK, Michael GJ, Romero IA. Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation. J Cereb Blood Flow Metab. 2014 Dec 17. doi: 10.1038/jcbfm.2014.207. [Epub ahead of print]
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.

MicroRNA are bits of genetic material that can influence the production of  protein from translation of the DNA in genes. We have previously reported that microRNA 155 (miR-155) can inhibit migration of white blood cells across blood vessels (Click here). In this study another Mir...Mir142 does a similar thing, but it blocks nuclear factor kappa B, which is involved in cytokine production and is also a target for some MS drugs.
CoI work of TeamG and chums

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