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Updated: May 24, 2025
An Acute Retinal Model for Evaluating Blood Retinal Barrier Breach and Potential Drugs for Treatment
Published on: September 13, 2016
cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia
Xiangyu Ge1, Xingfei Zhu1, Wei Liu1
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University, Guangzhou, 510060, China.
Insights
cGAMP activates the STING pathway, causing blood-retinal barrier breakdown and vision loss in diabetic retinopathy. Targeting microglia and the P2RX7 transporter offers a potential therapeutic strategy for these blinding diseases.
Area of Science:
- Ophthalmology
- Immunology
- Neuroscience
Background:
- Impairment of the inner blood-retinal barrier (iBRB) is implicated in blinding diseases like diabetic retinopathy (DR).
- The cGAS-STING pathway's role in neurovascular system damage, particularly in the retina, remains unclear.
- This study investigates the cGAMP-STING pathway's impact on iBRB integrity and retinal health.
Purpose of the Study:
- To elucidate the mechanism by which cGAMP affects the iBRB and causes retinal degeneration.
- To identify the cellular targets and molecular transporters involved in cGAMP-mediated retinal damage.
- To evaluate the therapeutic potential of targeting the P2RX7 transporter in DR.
Main Methods:
- Analysis of extracellular cGAMP and STING pathway activation in human PDR samples and db/db diabetic mice.
- Histological, molecular, bioinformatic, and behavioral assessments of cGAMP's effects on iBRB.
- Single-cell RNA sequencing to identify cGAMP-responsive retinal cells and evaluation of P2RX7's role using inhibitors and deficient mice.
Main Results:
- Elevated cGAMP and STING activation were observed in PDR patients and diabetic mice.
- cGAMP administration induced STING-dependent iBRB breakdown and neurodegeneration, with microglia identified as key responders.
- P2RX7 was identified as the transporter for cGAMP into microglia, mediating STING activation; its inhibition protected the iBRB and improved neuronal survival in diabetic mice.
Conclusions:
- cGAMP-STING pathway activation, mediated by P2RX7 transport into microglia, drives iBRB breakdown in retinal diseases.
- Targeting microglia and the P2RX7 transporter presents a promising therapeutic avenue for conditions involving iBRB impairment.
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.
