Summary: Glaucoma is the leading cause of irreversible blindness and is characterized by the death of retinal ganglion cells (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-1α (IL-1α), and tumor necrosis factor α (TNF-α), three cytokines necessary and sufficient to drive the formation of A1 astrocytes. Upregulation of these cytokines occurs first in CD11b+ CD11c+ cells followed by CD11b+ CD11c− cells. Ablation of this pathway, by either genetic deletions of C1qa, IL-1α, and TNF-α, 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.
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