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

Cell Rep. 2020 Nov 3;33(5):108271. doi: 10.1016/j.celrep.2020.108271.


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.

Keywords: A1 reactive astrocyte; Glucagon-like peptide-1 receptor (GLP-1R) agonsit; NLY01; astrogliosis; glaucoma; intraocular pressure; microglia; neuroinflammation; neuroprotection; retinal ganglion cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / pathology
  • CD11b Antigen / metabolism
  • Cell Death
  • Complement C1q / metabolism
  • Female
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Inflammation / pathology*
  • Interleukin-1alpha / metabolism
  • Intraocular Pressure
  • Male
  • Mice, Inbred C57BL
  • Ocular Hypertension / complications*
  • Ocular Hypertension / physiopathology
  • Retinal Ganglion Cells / pathology
  • Retinal Neurons / pathology*
  • Tumor Necrosis Factor-alpha / metabolism


  • CD11b Antigen
  • Glucagon-Like Peptide-1 Receptor
  • Interleukin-1alpha
  • Tumor Necrosis Factor-alpha
  • Complement C1q