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.
Jacob K Sterling  1 ,  Modupe O Adetunji  2 ,  Samyuktha Guttha  2 ,  Albert R Bargoud  2 ,  Katherine E Uyhazi  2 ,  Ahmara G Ross  2 ,  Joshua L Dunaief  2 ,  Qi N Cui  3
Affiliations
  • 1. FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 2. FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • 3. FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 33147455 DOI: 10.1016/j.celrep.2020.108271
Abstract

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.
Products