C5a/CD88 signaling alters blood-brain barrier integrity in lupus through nuclear factor-κB

J Neurochem. 2011 Dec;119(5):1041-51. doi: 10.1111/j.1471-4159.2011.07490.x. Epub 2011 Oct 20.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology*
  • Cell Line, Transformed
  • Complement C5a / physiology*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Lupus Erythematosus, Systemic / metabolism*
  • Lupus Erythematosus, Systemic / pathology*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • Primary Cell Culture
  • Receptor, Anaphylatoxin C5a / physiology*
  • Signal Transduction / physiology*

Substances

  • NF-kappa B
  • Receptor, Anaphylatoxin C5a
  • Complement C5a