GLP-1R agonist NLY01 reduces retinal inflammation, astrocyte reactivity, and retinal ganglion cell death secondary to ocular hypertension

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by the death of retinal ganglion cells. Reduction of intraocular pressure (IOP) is the only therapeutic mechanism available to slow disease progression. However, glaucoma can continue to progress despite normalization of IOP. New treatments are needed to reduce vision loss and improve outcomes for patients who have exhausted existing therapeutic avenues. Recent studies have implicated neuroinflammation in the pathogenesis of neurodegenerative diseases of both the retina and the brain, including glaucoma and Parkinson's disease. Pro-inflammatory A1 astrocytes contribute to neuronal cell death in multiple disease processes and have been targeted therapeutically in mouse models of Parkinson's disease. Microglial release of pro-inflammatory cytokines C1q, IL-1α, and TNF-α is sufficient to drive the formation of A1 astrocytes. The role of A1 astrocytes in glaucoma pathogenesis has not been explored. Using a mouse model of glaucoma, we demonstrated that IOP elevation was sufficient to trigger production of C1q, IL-1α, and TNF-α by infiltrating macrophages followed by resident microglia. These three cytokines drove the formation of A1 astrocytes in the retina. Furthermore, cytokine production and A1 astrocyte transformation persisted following IOP normalization. Ablation of this pathway, by either genetic deletions of C1q, IL-1α, and TNF-α, or treatment with glucagon-like peptide-1 receptor agonist NLY01, reduced A1 astrocyte transformation and RGC death. Together, these results highlight a new neuroinflammatory mechanism behind glaucomatous neurodegeneration that can be therapeutically targeted by NLY01 administration.

The role of glia in the physiology and pharmacology of glucagon‐like peptide‐1: implications for obesity, diabetes, neurodegeneration and glaucoma

“…In a recent study by our group, we showed that treatment with NLY01 reduced production of all three pro-inflammatory cytokines by microglia/macrophages in this mouse model of glaucoma (Sterling et al, 2020a). Further, NLY01 treatment prevented A1 astrocyte transformation and rescued retinal ganglia cells in these animals (Sterling et al, 2020a). GLP-1R agonists reduce blood-retina barrier (BRB) permeability by down-regulating pro-inflammatory cytokines and protect tight junctions in rodent models of diabetes (Simo & Hernandez, 2017).…”

“…The accumulating evidence is suggestive of a complex putative multicellular anti-inflammatory and neuroprotective action of GLP-1R agonists on neurons, astrocytes and microglia. GLP-1, glucagon-like peptide-1; RGC, retinal ganglion cell rescued retinal ganglia cells in a microbead-induced mouse model of acute, hypertensive glaucoma (Guttenplan et al, 2020;Sterling et al, 2020a). In a recent study by our group, we showed that treatment with NLY01 reduced production of all three pro-inflammatory cytokines by microglia/macrophages in this mouse model of glaucoma (Sterling et al, 2020a).…”

“…In the retina, intraocular pressure elevation stimulates microglia/macrophages (CD11b + cells) to produce IL‐1α, TNF‐α and C1q, a trio of pro‐inflammatory cytokines necessary and sufficient to induce A1 astrocyte transformation and retinal ganglia cell death (Guttenplan et al, 2020; Liddelow et al, 2017; Sterling et al, 2020a). Knocking out the cytokine genes or neutralizing antibodies to these cytokines rescued retinal ganglia cells in a microbead‐induced mouse model of acute, hypertensive glaucoma (Guttenplan et al, 2020; Sterling et al, 2020a). In a recent study by our group, we showed that treatment with NLY01 reduced production of all three pro‐inflammatory cytokines by microglia/macrophages in this mouse model of glaucoma (Sterling et al, 2020a).…”

“…Knocking out the cytokine genes or neutralizing antibodies to these cytokines rescued retinal ganglia cells in a microbead‐induced mouse model of acute, hypertensive glaucoma (Guttenplan et al, 2020; Sterling et al, 2020a). In a recent study by our group, we showed that treatment with NLY01 reduced production of all three pro‐inflammatory cytokines by microglia/macrophages in this mouse model of glaucoma (Sterling et al, 2020a). Further, NLY01 treatment prevented A1 astrocyte transformation and rescued retinal ganglia cells in these animals (Sterling et al, 2020a).…”

“…Indeed, NLY01 is a pegylated form of exendin-4 with a long half-life in both non-human primates (88 h) and mice (38 h), where it can efficiently penetrate the BBB resulting in high concentration in the CNS (Yun et al, 2018). In mouse models of Parkinson's disease and in culture, NLY01 was shown to prevent neuron death by reducing IL-1α, TNF-α and C1q release from microglia, thereby preventing astrocyte conversion to a neurotoxic (A1) phenotype (Yun et al, 2018) In the retina, intraocular pressure elevation stimulates microglia/ macrophages (CD11b + cells) to produce IL-1α, TNF-α and C1q, a trio of pro-inflammatory cytokines necessary and sufficient to induce A1 astrocyte transformation and retinal ganglia cell death (Guttenplan et al, 2020;Liddelow et al, 2017;Sterling et al, 2020a). Knocking out the cytokine genes or neutralizing antibodies to these cytokines F I G U R E 2 A growing body of preclinical evidence is supporting the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonism may be a novel therapeutic tool to treat and/or prevent the onset of multiple neurodegenerative diseases.…”