ArticleJournal of neuroinflammation2025
cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia.
Article in Journal of neuroinflammation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- cGAS-STING pathway modulation: A new hope for neural regeneration.Neural regeneration research · 2026Article
- Extracellular cGAMP in health and disease.Molecular biomedicine · 2026Review
- The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.Cell communication and signaling : CCS · 2026Review
- Aberrant STING signalling promotes endothelial dysfunction and neurovascular injury in diabetic retinopathy.Diabetologia · 2026Article
- Targeting P2X7R Protects the Retina Against High-Altitude Hypoxia via NLRP3-Mediated Pyroptosis Suppression.Molecular neurobiology · 2026Article
- Role of the cGAS-STING signaling pathway in diabetes mellitus and its complications: from mechanisms to therapeutics.Frontiers in pharmacology · 2026Review
- Wogonin improves high glucose-induced ARPE-19 cell damage by inhibiting ferroptosis via suppressing the cGAS-STING pathway.In vitro cellular & developmental biology. Animal · 2025Article
- STING activates ZBP1-mediated PANoptosis to defend against HSV-1 retinal infection.Journal of neuroinflammation · 2025Article
- cGAS-STING pathway-mediated inflammatory response and its role in corneal fibrosis mechanisms.Molecular biology reports · 2025Review
- Therapeutic potential of P2X7 receptor in retinal diseases.Purinergic signalling · 2025Review
- Identification and validation of key mitophagy-related biomarkers in the pathogenesis of proliferative diabetic retinopathy.Frontiers in endocrinology · 2025Article
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15 authors.
Funding
Abstract
backgroundImpairment of the inner blood-retinal barrier (iBRB) leads to various blinding diseases including diabetic retinopathy (DR). The cGAS-STING pathway has emerged as a driving force of cardiovascular destruction, but its impact on the neurovascular system is unclear. Here, we show that cGAMP, the endogenous STING agonist, causes iBRB breakdown and retinal degeneration thorough P2RX7-mediated transport into microglia.
methodsExtracellular cGAMP and STING pathway were determined in tissue samples from patients with proliferative DR (PDR) and db/db diabetic mice. Histological, molecular, bioinformatic and behavioral analysis accessed effects of cGAMP on iBRB. Single-cell RNA sequencing identified the primary retinal cell type responsive to cGAMP. Specific inhibitors and P2RX7-deficienct mice were used to evaluate P2RX7' role as a cGAMP transporter. The therapeutic effects of P2RX7 inhibitor were tested in db/db mice.
resultscGAMP was detected in the aqueous humor of patients with PDR and elevated in the vitreous humor with STING activation in db/db mouse retinas. cGAMP administration led to STING-dependent iBRB breakdown and neuron degeneration. Microglia were the primary cells responding to cGAMP, essential for cGAMP-induced iBRB breakdown and visual impairment. The ATP-gated P2RX7 transporter was required for cGAMP import and STING activation in retinal microglia. Contrary to previous thought that mouse P2RX7 nonselectively transports cGAMP only at extremely high ATP concentrations, human P2RX7 directly binds to cGAMP and activates STING under physiological conditions. Clinically, cGAMP-induced microglial signature was recapitulated in fibrovascular membranes from patients with PDR, with P2RX7 being predominantly expressed in microglia. Inhibiting P2RX7 reduced cGAMP-STING activation, protected iBRB and improved neuron survival in diabetic mouse retinas.
conclusionsOur study reveals a mechanism for cGAMP-mediated iBRB breakdown and suggests that targeting microglia and P2RX7 may mitigate the deleterious effects of STING activation in retinal diseases linked to iBRB impairment.
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