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

Jacob K Sterling,Modupe O Adetunji,Samyuktha Guttha,Albert R Bargoud,Katherine E Uyhazi,Ahmara G Ross,Joshua L Dunaief,Qi N Cui

doi:10.1016/j.celrep.2020.108271

Jacob K Sterling, Modupe O Adetunji + Show 6 more

Open Access

https://doi.org/10.1016/j.celrep.2020.108271

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Abstract

SUMMARYGlaucoma 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.

Highlights

Glaucoma is characterized by the death of retinal ganglion cells (RGCs), leading to permanent vision loss
Microbead-injected eyes in both WT and triple knockout (TKO) animals had elevated intraocular pressure (IOP) beginning at 7 days post-injection compared to balanced salt solution (BSS)-injected eyes (Figure 1A)
Cell-type enrichment for all fractions used in the paper were validated by Quantitative PCR (qPCR) (Figures S1B and S1C)

Summary

Introduction

Glaucoma is characterized by the death of retinal ganglion cells (RGCs), leading to permanent vision loss. Reactive astrocytes are observed in multiple neurodegenerative diseases (Liddelow et al, 2017; Yun et al, 2018). Astrocytes serve a wide variety of roles They contribute to neurotransmitter recycling, neuronal metabolism, and formation of the blood-brain and blood-retina barriers (Clarke and Barres, 2013; Liddelow and Barres, 2017). Astrocytes are found exclusively in the ganglion cell layer, comingled with RGCs (Vecino et al, 2016) In response to both local and systemic stimuli, astrocytes can adopt reactive forms, A1 pro-inflammatory or A2 neuroprotective, both of which have been transcriptionally defined (Zamanian et al, 2012). While A1 astrocytes have been implicated in multiple neurodegenerative diseases (Liddelow et al, 2017; Yun et al, 2018), their contribution to glaucoma is only beginning to be explored

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