A local complement response by RPE causes early-stage macular degeneration

Area of Science:

• Ophthalmology
• Cell Biology
• Immunology

Background:

• Inherited and age-related macular degenerations (AMD) cause vision loss, with sub-retinal pigment epithelium (RPE) basal deposits as an early sign.
• Genetic studies suggest a role for the complement system in AMD, but direct functional links are undefined.

Purpose of the Study:

• Investigate the RPE's role in early inherited macular degeneration (MD) pathogenesis using a mouse model with a mutation in EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1).
• Determine the functional connection between EFEMP1 mutations, complement activation, and basal deposit formation in the RPE.

Main Methods:

• Utilized primary RPE cells from a mouse model of inherited MD carrying the p.R345W mutation in EFEMP1.
• Assessed basal deposit formation in vitro and analyzed the involvement of EFEMP1(R345W) and complement components (C3a, C5a).
• Investigated the impact of EFEMP1(R345W) and C3a on extracellular matrix (ECM) turnover and cytokine release (IL-6, IL-1B).

Main Results:

• Efemp1(R345W) RPE cells formed sub-RPE deposits in vitro, mimicking in vivo basal deposits.
• Deposit formation was mediated by EFEMP1(R345W) and C3a, but not C5a.
• Increased C3a production stimulated IL-6 and IL-1B release, contributing to deposit formation.
• Abnormal ECM and inhibited matrix metalloproteinase 2 by EFEMP1(R345W) and C3a contributed to increased complement activation.

Conclusions:

• Provides the first direct evidence that locally produced complement components by RPE cells are implicated in basal deposit formation.
• Suggests that C3a generated by RPE is a potential therapeutic target for EFEMP1-associated MD and AMD.
• Highlights the interplay between ECM abnormalities, complement activation, and inflammatory responses in early MD pathogenesis.