title: Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells.
abstract: Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0 · 05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Eadon
authors.forename: Alexander
authors.initials: A
authors.lastname: Jacob
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Cunningham
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Jessy J
authors.initials: JJ
authors.lastname: Alexander
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010539:Permeability
chemical_list: D035683:MicroRNAs; D015936:Complement C5a
keywords: brain; complement; endothelial cells; inflammation; lupus; microRNA