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Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
Absence of functional alternative complement pathway alleviates lupus cerebritis
Jessy J Alexander1, Alexander Jacob, Paul Vezina
1Department of Medicine, University of Chicago, Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu
Abstract:
The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB-/-MRL/lpr) compared to fB-sufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16+/-0.02 vs. 0.35+/-0.13, p<0.03) was increased, while expression of p-PTEN (0.40+/-0.06 vs. 0.11+/-0.07, p<0.05) was decreased in fB-/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB-/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis.
Insights
The alternative complement pathway contributes to lupus cerebritis. Blocking this pathway with complement factor B deficiency reduced neuroinflammation and improved behavioral outcomes in lupus model mice.
Area of Science:
- Immunology
- Neuroscience
- Rheumatology
Background:
- The complement system, particularly the alternative pathway, plays a role in CNS diseases like lupus cerebritis.
- Understanding the specific contribution of the alternative pathway is crucial for targeted therapies.
Purpose of the Study:
- To investigate the role of the alternative complement pathway in lupus cerebritis using mice deficient in complement factor B (fB).
Main Methods:
- Studied MRL/lpr mice with and without complement factor B (fB-/-MRL/lpr vs. MRL/lpr).
- Assessed immune deposits, neutrophil infiltration, apoptosis, protein expression (p-Akt, p-PTEN), extracellular matrix components, and behavioral alterations.
Main Results:
- fB deficiency reduced immune deposits, neutrophil infiltration, and apoptosis in the brain.
- Absence of fB increased p-Akt and decreased p-PTEN expression, suggesting neuroprotection.
- Tissue integrity was maintained, and behavioral deficits were reduced in fB-deficient mice.
Conclusions:
- The alternative complement pathway is a key driver of CNS inflammation in lupus.
- Targeting the alternative pathway, specifically complement factor B, may be a promising therapeutic strategy for lupus cerebritis.
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