title: C5a/CD88 signaling alters blood-brain barrier integrity in lupus through nuclear factor-κB.
abstract: Inflammation is a key factor in a number of neurodegenerative diseases including systemic lupus erythematosus. The complement system is an important mechanism in initiating and amplifying inflammation. Our recent studies demonstrate that C5a, a protein fragment generated during complement activation could alter the blood-brain barrier integrity, and thereby disturb the brain microenvironment. To understand the mechanism by which this occurs, we examined the effects of C5a on apoptosis, translocation of nuclear factor-κB (NF-κb) and the expression of Iκbα, MAPK, CREB and TJ protein, zona occludens (ZO-1) in mouse brain endothelial cells. Apoptosis was examined by DNA laddering and caspase 3 activity and the distribution of the ZO-1 and the p65 subunit of NF-κB were determined by immunofluorescence. Inhibition of CD88 reduced translocation of NF-κb into the nucleus, altered ZO-1 at the interfaces of neighboring cells, decreased caspase 3 activity and prevented apoptosis in these cells. Our results indicate that signaling through CD88 regulates the blood-brain barrier in a NF-κb-dependent manner. These studies suggest that the C5a receptor, CD88 is a promising therapeutic target that will reduce NF-κb-signaling cascades in inflammatory settings.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jacob
authors.forename: Bradley
authors.initials: B
authors.lastname: Hack
authors.forename: Peili
authors.initials: P
authors.lastname: Chen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
authors.forename: Jessy J
authors.initials: JJ
authors.lastname: Alexander
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology*; D002461:Cell Line, Transformed; D015936:Complement C5a / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D061251:Primary Cell Culture; D044087:Receptor, Anaphylatoxin C5a / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a