Macrophage-associated profibrotic programs are associated with ERM formation in diabetic retinal diseases, and faricimab modulates macrophage polarization and fibrotic gene expression, providing a potential biological context for the observed antifibrotic effects of dual Ang2 and VEGFA inhibition.
Epiretinal membranes from patients with diabetic retinopathy showed greater macrophage infiltration than non-diabetic ERMs.
Tie2-expressing macrophages were enriched in diabetic retinopathy ERMs compared with non-diabetic ERMs.
PMA-induced differentiation of THP-1 cells into macrophages markedly upregulated inflammatory and profibrotic mediators.
Faricimab attenuated the expression of inflammatory and profibrotic macrophage genes in a concentration-dependent manner, with particularly prominent suppression of TGF-β1.
Faricimab reduced expression of profibrotic and extracellular matrix-related genes in the macrophage model.
Public transcriptomic datasets of human fibrovascular membranes showed coordinated upregulation of fibrosis-related gene networks and increased ACTA2 expression.
The authors conclude that macrophage-associated profibrotic programs are associated with ERM formation in diabetic retinal disease, and that faricimab modulates macrophage polarization and fibrotic gene expression.
This study looked at why scar-like membranes (epiretinal membranes) form on the retina in people with diabetic eye disease. Examining membranes removed during eye surgery, the researchers found more immune cells called macrophages in membranes from people with diabetic retinopathy than in those from people without diabetes. A subset of these macrophages carried a protein called Tie2, and these were more common in the diabetic membranes. Analysis of public gene-activity data from similar membranes also showed that genes involved in scarring and fibrosis were switched on together. The team then used a lab model of macrophages grown from a human cell line. When these cells were activated, they increased production of inflammatory and scar-promoting molecules, such as TGF-β1. Faricimab, a drug that blocks both Ang2 and VEGF-A and is used for diabetic eye disease, reduced the activity of these genes in a dose-dependent way, with the strongest effect on TGF-β1. It also lowered genes tied to scar tissue and tissue remodeling, such as ACTA2, fibronectin, MMP2, and MMP9. This research suggests that macrophage-driven scarring pathways may contribute to membrane formation in diabetic retinal disease, and that faricimab may dampen these pathways. However, the drug experiments were done in a cell-line model rather than in patients, so the findings offer a possible biological explanation for antifibrotic effects but do not show that faricimab prevents or treats these membranes in people.
Lee S, Kim D, Kim A, Kim H, Kim S, Lee J. (2026). Macrophage-Associated Profibrotic Programs in Diabetic Epiretinal Membrane and Their Modulation by Faricimab.. Investigative ophthalmology & visual science. https://doi.org/10.1167/iovs.67.12.51