Gain-of-Function Variant in STAT3 and Retinal Macular Edema: Insights into the IL-6 R/JAK/STAT3 Pathway in Retinal Pigment Epithelium.

Abstract

Purpose: The IL-6 R/JAK/STAT3 signaling pathway is implicated in non-infectious uveitis-associated macular edema, and its inhibition using monoclonal anti-IL-6 receptor therapy has been associated with clinical improvement. However, the underlying pathogenic mechanisms remain unclear. In this study, we investigated the pathological effects of a STAT3 gain-of-function (GOF) variant p.L387R identified in a family with immune dysregulation syndrome and severe retinal vasculitis and macular edema.

Methods: Primary retinal pigment epithelial (RPE) cells were transduced with STAT3 wildtype (WT), the retinal disease-associated familial STAT3 GOF variant p.L387R, or another pathogenic STAT3 GOF variant (p.Y360C) linked to immune dysregulation without retinal involvement. Cells were subsequently stimulated with IL-6 and IFN-α. RNA sequencing was performed to analyze gene expression differences, particularly related to cytokines, chemokines, and factors associated with RPE barrier permeability. Additionally, the expression of tight junction proteins involved in the blood-retinal barrier integrity was assessed. The efficacy of JAK inhibitors to modulate hyperactivation of the IL-6 R/JAK/STAT3 pathway was also evaluated.

Results: Compared with WT and STAT3 p.Y360C variant-expressing cells, those expressing STAT3 p.L387R variant produced significantly elevated levels of IL-6, CCL2, and VEGF-A, which are known contributors to vascular leakage in retinal endothelial cells. Treatment with JAK1/2 inhibitors effectively reduced SOCS3 overexpression in STAT3 GOF RPE cells.

Conclusion: The pathogenic STAT3 p.L387R GOF variant enhances inflammatory cytokine production in human primary RPE cells, potentially exacerbating retinal vascular leakage and macular edema. These effects can be mitigated by JAK1/2 inhibition, highlighting a promising therapeutic strategy for retinal inflammation and associated edema.