title: Administration of the soluble complement inhibitor, Crry-Ig, reduces inflammation and aquaporin 4 expression in lupus cerebritis.
abstract: Changes in brain water and cerebral volume can lead to brain edema that may be one of the underlying causes of death in many neurological diseases. Cerebral water content is regulated by aquaporin 4 (AQ4) present in astrocytic end feet and around blood vessels. In systemic lupus erythematosus (SLE), magnetic resonance imaging (MRI) studies of the brain have demonstrated lesions with the prominent appearance of edema. Activation of complement may play a significant role in the pathogenesis of lupus cerebritis by causing inflammation that can lead to edema. In this study, the well-established MRL/lpr lupus mouse model was used to evaluate the role of complement in lupus cerebritis. IgG and C1q colocalized in perivascular deposits indicating that the blood-brain barrier was compromised. Both RNA and protein expressions of AQ4 were significantly increased in brains of MRL/lpr mice. Chronic administration of the soluble complement inhibitor, Crry-Ig, reduced inflammation as measured by decreased accumulation of IgG. In contrast to control MRL/lpr mice, AQ4 expression in complement inhibited MRL/lpr mice was not changed relative to untreated congenic controls. These results illustrate that complement activation in brains of lupus mice leads to enhanced AQ4 expression and inflammation. It is conceivable that increased AQ4 expression results in cerebral edema and hence complement inhibition may provide a new therapeutic option in inflammatory cerebral disorders such as lupus cerebritis.
authors.affiliation: Department of Medicine, Section of Nephrology, University of Chicago, Chicago, IL 60637, USA. jalexand@medicine.uchicago.edu
authors.forename: Jessy J
authors.initials: JJ
authors.lastname: Alexander
authors.forename: Lihua
authors.initials: L
authors.lastname: Bao
authors.forename: Alexander
authors.initials: A
authors.lastname: Jacob
authors.forename: Damien M
authors.initials: DM
authors.lastname: Kraus
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
mesh_terms: D000818:Animals; D051401:Aquaporin 4; D020346:Aquaporins / Q000037:antagonists & inhibitors / Q000235:genetics*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001483:Base Sequence; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003169:Complement Inactivator Proteins / Q000627:therapeutic use*; D017931:DNA Primers; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D007074:Immunoglobulin G; D007249:Inflammation / Q000517:prevention & control*; D020945:Lupus Vasculitis, Central Nervous System / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D020411:Oligonucleotide Array Sequence Analysis; D015345:Oligonucleotide Probes; D011951:Receptors, Complement / Q000627:therapeutic use*; D017463:Receptors, Complement 3b; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D020346:Aquaporins; D003169:Complement Inactivator Proteins; C081470:Cr1l protein, mouse; D017931:DNA Primers; D007074:Immunoglobulin G; D015345:Oligonucleotide Probes; D011951:Receptors, Complement; D017463:Receptors, Complement 3b