Abstract
Purpose :
Glaucoma, characterized by progressive retinal ganglion cell (RGC) death and optic nerve (ON) degeneration, is the second leading cause of irreversible blindness worldwide. CXCL10, which is a chemokine released by injured/infected cells, has a key role in cell-cell communication by binding to its receptor CXCR3 expressed on the membrane of its target cells. This study aims to investigate the role of the CXCL10/CXCR3 pathway in glaucomatous neurodegeneration.
Methods :
A glaucoma model was induced by injecting polystyrene microbeads into the anterior chamber of WT and CXCR3 deficient mice. Intraocular pressure (IOP) was measured using a tonometer. The expressions of CXCL10, C3 and C3aR were measured by qPCR. The localization of C3 and C3aR, and the numbers of RGC and axons were examined by immunostaining. Visual functions were evaluated by recording pattern electroretinogram, visual evoked potential and visual acuity.
Results :
CXCL10 expression was markedly increased at 5 days after microbeads injection. At 6 weeks after microbeads injection, CXCR3 deletion dramatically prevented RGC loss and alleviated axonal degeneration, although it did not change the IOP level. Consistently, visual functions assessed by pattern electroretinography, visual evoked potential and visual acuity were significantly preserved in CXCR3 deficient mice. Moreover, CXCR3 deletion attenuated the expressions of C3 in astrocytes and C3aR in RGCs of glaucomatous eyes. C3aR inhibitor treatment recapitulated the neuroprotective effects of the CXCR3 deletion.
Conclusions :
These data indicate that CXCR3 induces a toxic RGC-astrocyte crosstalk via CXCR3-mediated C3/C3aR signaling in glaucoma. CXCR3 blockade may be a favorable strategy in the treatment of glaucomatous neurodegeneration.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.