C3aR inhibition reduces neurodegeneration in experimental lupus.
Complement activation is an important aspect of systemic lupus erythematosus. In this study we investigated the role of C3a/C3a receptor (R) signaling in brains of the lupus model, MRL/lpr mice, by treating the mice with C3aR antagonist (a) from 13 to 19 weeks of age. C3aR mRNA (0.2 +/- 0.027 versus 0.56 +/- 0.19) and protein (0.16 +/- 0.09 versus 0.63 +/- 0.19) expression was increased in MRL/lpr brains compared with MRL+/+ controls. Apoptosis, a key feature in lupus brain, was significantly reduced by C3aRa treatment, as assessed by DNA laddering, TUNEL staining and caspase3 activity (48% of MRL/lpr mice). mRNA expression of proinflammatory molecules that cause apoptosis, TNFalpha (0.33 +/- 0.07 versus 0.15 +/- 0.1), MIP2 (3.8 +/- 1.3 versus 1.7 +/- 0.6), and INFgamma (4.8 +/- 1.0 versus 2.07 +/- 1.28) are reduced in MRL/lpr brains with C3aRa treatment. In line with these results, Western blotting demonstrates the significant increase in phosphorylation of survival molecules Akt and Erk, decrease in PTEN and reduced iNOS expression. INFgamma receptor (R) and AMPA-GluR1 co-localized, and concomitant with reduced INFgammaR expression, AMPAGluR1 expression was also decreased by C3aR antagonist. All of these variables that modulate neuronal excitability and regulate synaptic plasticity are C3aR dependent in the MRL/lpr brains and suggest a potential therapeutic role for C3aR inhibition in CNS lupus.
Jacob
A
A
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Bao
L
L
Brorson
J
J
Quigg
R J
RJ
Alexander
J J
JJ
D000818:Animals; D017209:Apoptosis; D003167:Complement Activation; D005911:Gliosis / Q000517:prevention & control; D007371:Interferon-gamma / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000150:complications* / Q000276:immunology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000517:prevention & control; D009474:Neurons / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D018091:Receptors, AMPA / Q000502:physiology; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction
D018091:Receptors, AMPA; D011951:Receptors, Complement; C085567:complement C3a receptor; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II