Inhibition of C5a receptor alleviates experimental CNS lupus.
To investigate the role of C5a generated on complement activation in brain, the lupus model, MRL/lpr mice were treated with C5a receptor(R) antagonist (ant). Neutrophil infiltration, ICAM, TNF-alpha and iNOS mRNA expression, neuronal apoptosis and the expression of p-JNK, pSTAT1 and p-Erk were reduced and p-Akt increased on C5aR inhibition in MRL/lpr brains. MRL/lpr serum caused increased apoptosis in neurons showing that lupus had a direct effect on these cells. C5aRant pretreatment prevented the lupus serum induced loss of neuronal cells. Our findings demonstrate for the first time that C5a/C5aR signaling plays an important role in the pathogenesis of CNS lupus.
Jacob
Alexander
A
Department of Medicine, University of Chicago, Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu
Hack
Bradley
B
Bai
Tao
T
Brorson
James R
JR
Quigg
Richard J
RJ
Alexander
Jessy J
JJ
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D015936:Complement C5a / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D020287:In Situ Nick-End Labeling / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020945:Lupus Vasculitis, Central Nervous System / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009474:Neurons / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D017304:Annexin A5; C112335:C5aRAD; D015815:Cell Adhesion Molecules; D054426:Chemokine CXCL2; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015936:Complement C5a; D052247:Nitric Oxide Synthase Type II