A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

Area of Science:

• Ophthalmology
• Immunology
• Molecular Biology

Background:

• The complement system is vital for retinal homeostasis.
• Complement protein deposition is observed in diabetic retinopathy (DR), but its role is unclear.
• Understanding complement's role in DR pathogenesis is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of the complement system in diabetic retinopathy (DR).
• To evaluate complement protein levels and gene expression in vitreous humor and serum of DR patients.
• To explore the involvement of microglia and the alternative complement pathway in DR.

Main Methods:

• Quantified major complement proteins (C3, C1q, C4b, CFB, CFH) and activated fragments in vitreous and serum.
• Analyzed pro- and anti-angiogenic gene expression in PDR, NPDR, and control samples.
• Assessed pro-inflammatory cytokines and matrix metalloproteinases in vitreous humor.
• Examined C3 deposition, basement membrane thickness, and CFH/microglia co-localization in retinal tissues.

Main Results:

• Elevated C3, C3bα', and CFH levels in PDR vitreous indicate alternative complement pathway activation.
• Upregulation of angiogenic genes and downregulation of anti-angiogenic genes in DR.
• Increased MMP9, IL8, sPECAM, and decreased IL-10 in PDR vitreous suggest microglial involvement.
• CFH expression co-localized with CD11b+ microglia in diabetic retinas, suggesting microglia as a CFH source.

Conclusions:

• The alternative complement pathway plays a significant role in DR pathogenesis and progression.
• Microglia are implicated in DR by producing CFH, potentially as a feedback mechanism.
• Targeting the alternative complement pathway and microglial activation may offer therapeutic strategies for DR.