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Publication

March 11, 2025 • ✎ STRIA TECH

cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia

Topics:

Diabetic Retinopathy

Neuroinflammation

Neurovascular Injury

Vascular and Metabolic Disease: Diabetic Retinopathy and Stroke

Publication

Journal of Neuroinflammation (Mar 01, 2025) cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into micrglia

Ge X, Zhu X, Liu W, Li M, Zhang Z, Zou M, Deng M, Cui H, Chen Z, Wang L, Hu X, Ju R, Tang X, Ding X, Gong L

DOI: 10.1186/s12974-025-03391-w >>

In diabetic retinopathy, the breakdown of the inner blood-retinal barrier leads to retinal degeneration. This study explores the contribution of a key player in immune signaling, the cGAS-STING pathway. Researchers found elevated levels of cGAMP, an endogenous STING activator, both in patients with proliferative diabetic retinopathy and in diabetic mice. cGAMP is transported into retinal microglia via the P2RX7 receptor. This triggers damage to the inner blood-retinal barrier, neuronal degeneration, and vision impairment. Blocking P2RX7 reduced STING activation, preserved inner blood-retinal barrier integrity, and improved neuronal survival in diabetic models, highlighting its therapeutic potential. The OptoDrum system was employed to assess visual acuity in mice. This helped quantifying the impact of cGAMP-induced retinal damage on visual behavior.

Background: Impairment 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. Methods: Extracellular 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. Results: cGAMP 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. Conclusions: Our 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.