Abstract
PURPOSE: Glaucoma is characterized by progressive retinal ganglion cell (RGC) death and optic nerve degeneration. Chemokines are a family of small, secreted proteins that mediate cell-cell communication, an essential process for maintaining microenvironmental homeostasis and regulating pathophysiological changes in multicellular organisms. However, the contribution of retina-derived chemokines to RGC loss in glaucoma remains poorly understood. METHODS: We reanalyzed a publicly available retinal bulk RNA sequencing dataset from a mouse model of glaucoma to identify differentially expressed chemokines. A mouse model of microbead-induced glaucoma and primary RGCs and astrocytes were used to assess the role of the C-X-C motif chemokine ligand 10 (CXCL10)/C-X-C motif chemokine receptor 3 (CXCR3) axis in disease. RESULTS: Several chemokines were significantly upregulated during disease progression, including CXCL10, previously implicated in neurodegeneration. In the microbead model, CXCL10 expression increased markedly by day 5 post-injection. At 6 weeks, deletion of CXCR3, the receptor for CXCL10, significantly prevented RGC loss and axonal degeneration without affecting intraocular pressure (IOP). Visual function, assessed by pattern electroretinography and visual acuity, was preserved in CXCR3-deficient mice. Mechanistically, CXCL10/CXCR3 signaling upregulated complement component 3 (C3) in astrocytes and C3a receptor (C3aR) in RGCs, driving toxic astrocyte-RGC crosstalk. Gene therapy using intravitreal injection of adeno-associated virus-mediated dominant-negative CXCL10 or pharmacological blockade of C3aR effectively reduced RGC loss. CONCLUSIONS: CXCL10/CXCR3 signaling is a key mediator of RGC loss in glaucoma. Targeting this pathway, along with its upregulated C3/C3aR axis, represents a promising IOP-independent therapeutic strategy for glaucoma.