Complement-dependent apoptosis and inflammatory gene changes in murine lupus cerebritis

Area of Science:

• Neuroimmunology
• Rheumatology
• Molecular Biology

Background:

• Systemic lupus erythematosus (SLE) can affect the central nervous system, leading to lupus cerebritis.
• The role of the complement system in SLE-induced neuroinflammation and apoptosis is not fully understood.

Purpose of the Study:

• To investigate the role of complement activation in the brains of MRL/lpr lupus mouse model.
• To evaluate the therapeutic potential of complement inhibition in lupus cerebritis.

Main Methods:

• Administration of CR1-related y (Crry) via transgene and fusion protein to inhibit complement C3 convertase.
• Assessment of complement deposition (C3, C9), apoptosis (TUNEL, DNA laddering, caspase-3), and inflammatory markers (TNFR1, iNOS, ICAM-1, AMPA-GluR) in mouse brains.
• Microarray analysis to identify complement-dependent gene expression changes.

Main Results:

• Significant deposition of C3 and C9 in lupus mouse brains, indicative of complement activation.
• Crry treatment markedly reduced complement deposition, apoptosis, and expression of inflammatory molecules (TNFR1, iNOS, ICAM-1).
• Complement activation was found to up-regulate glutamate receptor (AMPA-GluR) expression in lupus brains.

Conclusions:

• Complement activation plays a critical role in inducing apoptosis and inflammation in lupus cerebritis.
• Inhibition of complement activation by Crry effectively ameliorated these pathological changes.
• Complement inhibition represents a promising therapeutic strategy for treating lupus cerebritis.