Abstract
Abstract
Glaucoma is a leading cause of irreversible blindness worldwide, yet available treatments fail to prevent disease progression for all patients. It is characterized by a progressive dysfunction and loss of retinal ganglion cells. Neuroinflammation has been recognized as an underlying neurodegenerative mechanism of glaucoma in animal models and human post-mortem samples, and targeting neuroinflammation may provide additional means to neuroprotection. Galectin-3, a pro-inflammatory mediator encoded by the
LGALS3
gene in humans, holds promise as a treatable target as its pharmacological and genetic inhibition is neuroprotective in multiple models of experimental glaucoma. However, the role of Galectin-3 in glaucoma remains unclear, particularly whether its emergence is a consequence of degeneration, or occurs at earlier time points. To address these knowledge gaps, we labeled IBA1, GFAP, and Galectin-3 in retina sections at early glaucoma stages in the rat bead glaucoma model, and in human retina from glaucoma donors. In the rat, IBA1 volume, but not GFAP, increased at an early, pre-degenerative timepoint. Accompanying this, we identified a significant increase of Galectin-3/IBA1 colocalization compared to control at the same timepoint, supporting the upregulation of Galectin-3 in early inflammation, preceding retinal ganglion cell degeneration in experimental glaucoma. However, a significant increase in Galectin-3/GFAP colocalization compared to control at the same timepoint in the rat additionally associates Galectin-3 production with astrocytes and Müller glia. This Galectin-3 to Müller glia relationship was significantly pronounced in human glaucomatous retina, predominating over microglia co-labelling. We further demonstarted that human MIO-M1 Müller glia in vitro express Galectin-3, but this is not altered in response to glaucoma relevant stimuli (TNF-α or mild-metabolic stress from rotenone). Instead, Galectin-3 expression was altered in phagocytosing states from exposure to
E. coli
particles, brain synaptosomes, or apoptotic neuronal debris. These findings provide further insight into Galectin-3 and gross inflammatory responses in glaucoma pathology.