GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension

Glaucomais the leadingcauseof irreversibleblindness andis characterizedbythedeath of retinalganglioncells (RGCs). Recent studies have implicated pro-inflammatory microglia, macrophages, and A1 astrocytes in the pathogenesis of neurodegenerative diseases. The role of pro-inflammatory, neurotoxic A1 astrocytes in glaucoma is just beginning to be explored. Using a mouse model of glaucoma, we demonstrate that ocular hypertension is sufficient to trigger production of C1q, interleukin-1 alpha (IL-1 alpha), and tumor necrosis factor alpha (TNF-alpha), three cytokines necessary and sufficient to drive the formation of A1 astrocytes. Upregulationof these cytokines occurs first in CD11b(+) CD11c(+) cells followed by CD11b(+) CD11c(-) cells. Ablation of this pathway, by either genetic deletions of C1qa, IL-1 alpha, and TNF-alpha, or treatment with glucagon-like peptide-1 receptor agonist NLY01, reduces A1 astrocyte transformation and RGC death. Together, these results highlight a neuroinflammatory mechanism of glaucomatous neurodegeneration that can be therapeutically targeted by NLY01 administration.