STING activation induces polarized cytokine secretion of IFN-β and IL-17A promoting photoreceptor death and choroidal disruption in age-related macular degeneration

TL;DR

The STING pathway contributes to AMD by triggering harmful inflammation and cell death in the retina, offering a new therapeutic target.

Contribution

The study identifies STING as a master regulator of multiple AMD pathologies through spatially organized inflammation.

Findings

STING activation leads to polarized cytokine secretion, causing photoreceptor death and choroidal disruption.

Pharmacological and genetic inhibition of STING rescues AMD-like pathologies in mouse models.

STING exhibits biphasic functionality, offering cytoprotection in healthy tissue but driving inflammation in AMD.

Abstract

Age-related macular degeneration (AMD) represents one of the therapeutic challenges of aging eye diseases. Our investigation reveals the stimulator of interferon genes (STING) pathway as an orchestrator of immune-mediated retinal degeneration, exhibiting biphasic, stage-dependent functionality—providing cytoprotection in healthy tissue but driving pathogenic inflammation during early AMD progression. Through immunohistochemical analysis of human eyes, we demonstrate stage-dependent cytoplasmic STING upregulation with parallel IFN-β activation. Using patient-derived induced pluripotent stem cells-retinal pigment epithelium (iPSC-RPE) from AMD siblings, we discovered polarized cytokine secretion: apical IFN-β triggers photoreceptor apoptosis in human retinal organoids, while basal IL-17A compromises choroidal neovascularization. The Cryba1 conditional knockout (cKO) AMD-like mouse model confirms STING-driven IL-17A expression, while Il17a knock-in mice substantiate vascular alterations. STING activation establishes a pathogenic feed-forward loop between interferons and IL-17A. Single-cell transcriptomics following AAV2-mediated IFN-β overexpression reveals metabolic and phototransduction dysregulation. Both pharmacological STING inhibition with SN-011 and genetic approaches demonstrate therapeutic rescue. Cryba1/Sting double heterozygous (dhet) mice maintain homeostatic gene expression preserving retinal architecture and function. These findings establish STING as the master regulator simultaneously controlling multiple AMD pathologies through spatially organized inflammation, transforming from protective surveillance to pathogenic driver, and identifying a unified therapeutic target with demonstrated functional rescue across multiple experimental paradigms.

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