Suppression of Retinal Neovascularization by Anti-CCR3 Treatment in an Oxygen-Induced Retinopathy Model in Mice

Abstract

Purpose: To investigate the association between retinal neovascularization and the CC chemokine receptor-3 (CCR3) in a mouse model of oxygen-induced retinopathy (OIR). Methods: An OIR model in C57BL/6J mice was used as a retinal neovascularization model. An enzyme-linked immunosorbent assay was performed to evaluate the chronological change in vascular endothelial growth factor A (VEGF-A) and eotaxin expressions. CCR3 and VEGF subtype expression in the retina was examined using real-time RT-PCR, and CCR3, eotaxin, VEGF-A, and CD31 expression was examined immunohistochemically. A CCR3 neutralizing antibody (Ab) was injected into the vitreous humor on both postnatal days 12 (P12) and 14 (P14). Retinal neovascularizations were quantified by measurement of the percentages of neovascular area. Results: The mean eotaxin and VEGF-A protein level was significantly downregulated at P10 and P12 and was significantly upregulated at P14 and P17 (p < 0.05). CCR3 mRNA expression was significantly upregulated at P12 (p < 0.05). VEGF164 mRNA expression was significantly upregulated at P14 (p < 0.05). The areas of vaso-obliteration and neovascularization were significantly suppressed in anti-CCR3 Ab-treated eyes (p < 0.05). Anti-CCR3 Ab treatment suppressed VEGF and eotaxin but not monocyte chemoattractant protein-1. And VEGF 164 mRNA but not VEGF120 mRNA was suppressed by anti-CCR3 Ab treatment. Conclusions: The present data suggest that anti-CCR3 treatment can suppress retinal neovascularization. Anti-CCR3 treatment may have potential as a new therapy for retinopathies with retinal neovascularization such as diabetic retinopathy and retinopathy of prematurity.

Beyond VEGF: Targeting Inflammation and Other Pathways for Treatment of Retinal Disease

“…AKST4290 is an oral drug developed by Alkahest, designed to block the chemokine eotaxin from binding to its receptor, C-C motif chemokine receptor 3 (CCR3) as a novel oral therapy for inflammation-mediated nAMD (NCT04331730) Hirahara et al 2017;Stewart et al, 2022). Vicasinabin (RG7774) is a cannabinoid 2 receptor (CB2R) agonist that could modulate pro-and anti-inflammatory signaling in cells, developed by Roche for the treatment of DR (NCT04265261).…”

Systemic Cytokines in Retinopathy of Prematurity

“…Nonetheless, a study revealed lower plasma eotaxin levels in the early neonatal period of premature infants being associated with clinically significant ROP [ 198 ], possibly reflecting phase 1 disease characterized by retinal vaso-obliteration. The biphasic pattern of eotaxin was also observed in a mouse OIR model, and the anti-CCR3 antibody was proven to be efficacious in suppressing pathological neovascularization [ 199 ].…”

The role of inflammation in immune system of diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications

“…AKST4290, an inhibitor of CC chemokine receptor-3 (CCR3), is a natural receptor for eotaxin. Wet age-related macular degeneration (wet AMD), as well as other neurological and immunological illnesses, is mostly a result of the pathophysiology of inflammation, immune cell recruitment, and neovascularization, which is regulated by CCR3 ( 175 ). The oral medication AKST4290, which works well in preventing eotaxin from attaching to its G-protein coupled receptor (GPCR) CCR3, increased the age-related macular degeneration BCVA score ( 176 ).…”