Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis

The role of complement activation in the brains of MRL/lpr lupus mice was determined using the potent C3 convertase inhibitor, CR1-related y (Crry), administered both as an overexpressing Crry transgene and as Crry-Ig. Prominent deposition of complement proteins C3 and C9 in brains of MRL/lpr mice w...

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Bibliographic Details
Published in:Journal of Immunology 2005-12, Vol.175 (12), p.8312-8319
Main Authors: Alexander, Jessy J, Jacob, Alexander, Bao, Lihua, Macdonald, R. Loch, Quigg, Richard J
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Brain
Complement Activation
Complement C3 - analysis
Complement C9 - analysis
Complement System Proteins - physiology
Gene Expression Profiling
Inflammation - genetics
Lupus Vulgaris - pathology
Mice
Mice, Inbred MRL lpr
RNA, Messenger - analysis
Up-Regulation
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Summary:The role of complement activation in the brains of MRL/lpr lupus mice was determined using the potent C3 convertase inhibitor, CR1-related y (Crry), administered both as an overexpressing Crry transgene and as Crry-Ig. Prominent deposition of complement proteins C3 and C9 in brains of MRL/lpr mice was indicative of complement activation and was significantly reduced by Crry. Apoptosis was determined in brain using different independent measures of apoptosis, including TUNEL staining, DNA laddering, and caspase-3 activity, all of which were markedly increased in lupus mice and could be blocked by inhibiting complement with Crry. Complement activation releases inflammatory mediators that can induce apoptosis. The mRNA for potentially proinflammatory proteins such as TNFR1, inducible NO synthase, and ICAM-1 were up-regulated in brains of lupus mice. Crry prevented the increased expression of these inflammatory molecules, indicating that the changes were complement dependent. Furthermore, microarray analysis revealed complement-dependent up-regulation of glutamate receptor (AMPA-GluR) expression in lupus brains, which was also validated for AMPA-GluR1 mRNA and protein. Our results clearly demonstrate that apoptosis is a prominent feature in lupus brains. Complement activation products either directly and/or indirectly through TNFR1, ICAM-1, inducible NO synthase, and AMPA-GluR, all of which were altered in MRL/lpr mouse brains, have the potential to induce such apoptosis. These findings present the exciting possibility that complement inhibition is a therapeutic option for lupus cerebritis.
ISSN:0022-1767
1550-6606
1365-2567
DOI:10.4049/jimmunol.175.12.8312