[Literature Interpretation] CXCR3 Deficiency Alleviates Retinal Ganglion Cell Loss by Regulating Neuron–Astrocyte Communication in a Mouse Model of Glaucoma
Release time:
2026-09-16
Foreword
In the field of glaucoma research, accurate and reproducible intraocular pressure (IOP) monitoring is a core component for evaluating disease progression and intervention efficacy. A recent study published in Investigative Ophthalmology & Visual Science, using a microbead-induced mouse model of glaucoma, revealed the key mediating role of the CXCL10/CXCR3 signaling pathway in retinal ganglion cell (RGC) loss. Notably, over a 6-week experimental period, this study measured IOP using a Tonolab rebound tonometer (Icare Finland Oy, Helsinki, Finland) at a fixed time each day (15:00–17:00), effectively reducing interference from diurnal fluctuations in the data and providing a solid guarantee for the reliability of the experimental results. With its advantages of convenient operation, minimal corneal damage in mice, and high measurement reproducibility, the Tonolab tonometer has become an ideal tool for IOP monitoring in animal models of glaucoma, helping researchers more accurately track disease progression and therapeutic response.
01 Research Background
Glaucoma is a multifactorial neurodegenerative disease characterized primarily by progressive retinal ganglion cell (RGC) loss and optic nerve (ON) degeneration, and it is the second leading cause of irreversible blindness worldwide.
Glaucoma progression is closely associated with elevated intraocular pressure (IOP), and IOP is currently the most extensively studied and the only modifiable risk factor for glaucoma. However, lowering IOP alone cannot completely halt glaucoma progression.
RGC loss is irreversible. Elucidating the mechanisms of injury and identifying interventions that can prevent RGC loss remain key unresolved issues. Using a microbead-induced glaucoma model, we further confirmed that the CXCL10/CXC chemokine receptor 3 (CXCR3) signaling pathway plays a key role in RGC loss by regulating complement component 3 (C3)/C3a receptor (C3aR) pathway-mediated neuron–astrocyte interactions. This study reanalyzed publicly available retinal transcriptome sequencing (RNA-seq) datasets from mouse models of glaucoma, focusing on changes in chemokine expression.
02 Methods
We reanalyzed a publicly available whole-retinal RNA-seq dataset from a mouse model of glaucoma to identify differentially expressed chemokines. We used a microbead-induced mouse glaucoma model, primary RGCs, and astrocytes to investigate the role of the CXC chemokine ligand 10 (CXCL10)/CXC chemokine receptor 3 (CXCR3) axis in disease.
Glaucoma models were established in 8–10-week-old mice by microbead injection: mice were anesthetized by intraperitoneal injection of 75 mg/kg pentobarbital sodium, received topical anesthesia with 0.5% proparacaine hydrochloride, and their pupils were dilated with 1% tropicamide and 2.5% phenylephrine hydrochloride. A corneal tunnel was made with a 27G needle, and then the following were sequentially injected into the anterior chamber using a 32G needle and a microsyringe (Hamilton Company, Reno, NV, USA):
• 2 µL of a 1-µm diameter polystyrene microbead suspension (containing 3.0 × 10⁷ microbeads; Polysciences, Warrington, PA, USA)
• 2 µL of a 6-µm diameter polystyrene microbead suspension (containing 6.3 × 10⁶ microbeads; Polysciences)
• 1 µL of phosphate-buffered saline (PBS) containing 30% Healon.
This method induces a moderate elevation in IOP that is maintained for at least 6 weeks. IOP was measured daily between 15:00 and 17:00 using a Tonolab rebound tonometer designed for mice and rats (Icare Finland Oy, Helsinki, Finland) at fixed time points to minimize interference from diurnal fluctuations.
Beginning on day 3 after microbead injection, mice received intraperitoneal injections of the C3aR antagonist SB290157 (20 mg/kg) or vehicle control (PBS containing 10% Tween 80 and 10% ethanol) once every 12 hours for 6 consecutive weeks.
03 Results
During disease progression, multiple chemokines, including CXCL10, were significantly upregulated; CXCL10 has previously been shown to be associated with neurodegeneration. In the microbead-induced model, CXCL10 expression was already significantly elevated on day 5 after injection.
At 6 weeks after surgery, knockout of CXCR3, the receptor for CXCL10, significantly reduced RGC loss and axonal degeneration without affecting IOP. Pattern electroretinography and visual acuity testing showed that visual function was preserved in CXCR3 knockout mice.
Mechanistically, CXCL10/CXCR3 signaling upregulates complement component 3 (C3) in astrocytes and C3a receptor (C3aR) in RGCs, mediating detrimental astrocyte–RGC crosstalk.
Gene therapy via intravitreal injection of adeno-associated virus (AAV)-mediated dominant-negative CXCL10, or pharmacological blockade of C3aR, effectively reduced RGC loss.
04 Conclusions
The CXCL10/CXCR3 signaling pathway is a key mediator of retinal ganglion cell (RGC) loss in glaucoma. Targeting this pathway and its downstream upregulated C3/C3aR signaling axis may represent a novel IOP-independent therapeutic strategy for glaucoma.
05 Publication Information
Authors: Fan Xia; Shuizhen Shi; Erick Palacios; Won-Kyu Ju; Hua Liu; Wenbo Zhang
Journal: Investigative Ophthalmology & Visual Science
November 2025, Vol. 66, 42.
doi: https://doi.org/10.1167/iovs.66.14.42
Original article link: https://iovs.arvojournals.org/article.aspx?articleid=2811100&resultClick=1
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