MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium

Cerutti, Camilla; Edwards, Laura J.; de Vries, Helga E.; Sharrack, Basil; Male, David K.; Romero, Ignacio A.

Abstract

Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation.

Citation

Cerutti, C., Edwards, L. J., de Vries, H. E., Sharrack, B., Male, D. K., & Romero, I. A. (2017). MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium. Scientific Reports, 7, Article 45284. https://doi.org/10.1038/srep45284

• Journal Article Type: Article
• Acceptance Date: Feb 23, 2017
• Online Publication Date: Mar 30, 2017
• Publication Date: Mar 30, 2017
• Deposit Date: Nov 12, 2019
• Publicly Available Date: Dec 20, 2019
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Article Number: 45284
• DOI: https://doi.org/10.1038/srep45284
• Public URL: https://nottingham-repository.worktribe.com/output/3236848
• Publisher URL: https://www.nature.com/articles/srep45284
• Additional Information: Received: 4 October 2016; Accepted: 23 February 2017; First Online: 30 March 2017; : The authors declare no competing financial interests.