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C3a Mediates Endothelial Barrier Disruption in Brain-Derived, but Not Retinal, Human Endothelial Cells
Hannah Nora Wolf1, Larissa Guempelein1, Juliane Schikora1
1Department of Experimental Ophthalmology, University Marburg, 35043 Marburg, Germany.
International Journal of Molecular Sciences
|October 26, 2024
Summary
Neuromyelitis optica spectrum disorder (NMOSD) involves pathological aquaporin-4 immunoglobulin G (AQP4-IgG). This study found retinal endothelial cells are more resistant to complement-induced barrier breakdown than brain cells, suggesting better protection in the eye.
Area of Science:
- Neuroimmunology
- Vascular Biology
- Complement System
Background:
- Neuromyelitis optica spectrum disorder (NMOSD) pathogenesis involves aquaporin-4 immunoglobulin G (AQP4-IgG) and complement anaphylatoxins (C3a, C5a).
- The effect of these factors on the retinal endothelial barrier is not well understood.
- Endothelial barrier integrity is crucial for preventing neuroinflammation and tissue damage.
Purpose of the Study:
- To investigate the differential susceptibility of human brain microvascular endothelial cells (HBMEC) and human retinal endothelial cells (HREC) to C3a- and C5a-mediated stress.
- To evaluate the impact of anaphylatoxins on endothelial barrier function and complement gene expression in brain and retinal endothelial cells.
- To explore the potential protective mechanisms of the retinal endothelial barrier in the context of NMOSD.
Main Methods:
- Real-time cell barrier analysis to assess endothelial permeability.
- Immunocytochemical staining and qPCR to analyze complement receptor expression and gene levels.
- IgG transmigration assays to model antibody transport across endothelial barriers.
- Exposure of HBMEC and HREC to varying concentrations of C3a and C5a.
Main Results:
- C3a induced concentration-dependent barrier breakdown in HBMEC, while HREC maintained integrity.
- C5a showed a protective effect against C3a-induced disruption in HBMEC.
- Anaphylatoxin treatment altered complement gene and protein expression differently in HBMEC and HREC.
- HREC displayed increased C5a receptor 1 (C5aR1) protein levels, suggesting adaptive responses.
Conclusions:
- The retinal endothelial barrier exhibits greater stability against anaphylatoxin-induced stress compared to the brain endothelial barrier.
- These findings suggest a potential mechanism for enhanced protection of the retina in NMOSD.
- Differential regulation of complement pathways in brain versus retinal endothelial cells may influence disease pathology.
