# C1q limits cystoid edema by maintaining basal β-catenin–dependent signaling and blood-retina barrier function

## TL;DR

This study explores how C1q helps prevent retinal swelling by supporting blood-retina barrier function and shows that a specific treatment can resolve the swelling.

## Contribution

The study introduces a new mouse model of retinal edema and identifies C1q's protective role in maintaining retinal barrier function.

## Key findings

- C1QA maintains β-catenin–dependent signaling and prevents retinal barrier dysfunction.
- Compound mutant mice lacking C1QA show worsened cystoid edema and neuroinflammation.
- Activating FZD4/LRP5 signaling resolves cystoid edema in the mouse model.

## Abstract

Macular edema (ME) can cause profound vision impairment and occurs in several prevalent retinal diseases, including diabetic retinopathy, choroidal neovascularization, retinal vein occlusion, and uveitis. Retinal edema typically results from dysfunction of the blood-retina barrier (BRB), which is associated with increased retinal expression of complement components. It is unclear whether the classical complement pathway has detrimental or protective roles in the context of BRB dysfunction. Here, we characterized Tspan12-KODBM (disrupted BRB maintenance) mice, a mouse model of cystoid edema generated by genetically and pharmacologically manipulating β-catenin–dependent norrin/frizzled-4 (FZD4) signaling. We assessed BRB function, cystoid edema, electroretinogram, and microglia activation outcomes in an aging study with WT, C1qa-KO, Tspan12-KODBM, and Tspan12-KODBM; C1qa-KO compound mutant mice. Phenotypic analyses and cell-based experiments indicated that C1QA contributes to maintaining basal β-catenin–dependent signaling and that the absence of C1QA exacerbates BRB dysfunction, cystoid edema, and neuroinflammation in Tspan12-KODBM; C1qa-KO compound mutant mice. Activation of β-catenin–dependent signaling by an anti-FZD4 and anti-LRP5 agonistic antibody modality achieved complete resolution of cystoid edema. This study shows that reducing or enhancing norrin/FZD4 signaling can increase or decrease cystoid edema, respectively, underscoring its potential as a therapeutic target in ME. Furthermore, this study provides insights into the contribution of C1QA to BRB maintenance.

This study introduces a mouse model of retinal cystoid edema, identifies roles of C1q, and shows that a FZD4/LRP5 agonist achieves resolution of cystoid edema.