Pathological P-Selectin Upregulation Promotes Retinal Ganglion Cell Degeneration Accompanied by T-Cell Recruitment in...

Glaucoma is a leading cause of irreversible blindness worldwide with an unclear pathogenesis. Accumulating evidence has indicated that adhesion molecule-mediated transvascular migration of T cells into the retina is involved in the disease process. Because P-selectin mediates adhesive interactions between leukocytes and endothelial cells, we sought to determine whether it participates in retinal immune cell recruitment and contributes to glaucoma pathogenesis.

Plasma soluble P-selectin was measured by ELISA in 125 patients and in an elevated IOP mouse model. Retinal P-selectin (Selp) and its ligand P-selectin glycoprotein ligand 1 (Selplg) expression was analyzed by public transcriptomics and RT-qPCR. After intravitreal injection of recombinant P-selectin, retinal ganglion cell (RGC) axonal damage and glial activation were assessed by immunohistochemistry, and retinal T-cell numbers by flow cytometry.

Circulating soluble P-selectin levels were significantly higher in patients with glaucoma than in controls (median [interquartile range], 24.25 ng/mL [19.29 ng/mL] vs. 15.82 ng/mL [12.17 ng/mL]; P < 0.001) and were positively correlated with disease severity. Consistently, in an elevated IOP-induced mouse model, circulating soluble P-selectin levels and retinal mRNA expression of Selp and Selplg were also significantly increased. Furthermore, intravitreal administration of recombinant murine P-selectin induced RGC degeneration, accompanied by increased T-lymphocyte recruitment and microglial activation.

Our findings suggest that P-selectin is associated with increased retinal T-cell abundance, glial activation, and RGC injury, supporting a potential link between P-selectin-associated immune alterations and glaucomatous neurodegeneration.