Neuropilin-1–Expressing Myeloid Cells Partake in Choroidal Neovascularization.

Abstract

Purpose : Neuropilin-1 (NRP1) is a transmembrane receptor mostly recognized for its role in neuronal and vascular guidance and as a coreceptor for VEGF165. A genetic variation in NRP1 is associated with decreased response to ranibizumab, suggesting that NRP1 plays a role in wet age-related macular degeneration (AMD). Given that myeloid cells accumulate at sites of choroidal neovascularization (CNV) and that NRP1 is highly expressed by myeloid cells, we sought to determine the function of myeloid-resident NRP-1 in the pathogenesis of neovascular AMD.

Methods : We quantified by ELISA levels of NRP1 ligands SEMA3A and VEGF-A in the vitreous of patients with active neovascular AMD. We ablated NRP1 specifically in myeloid cells by crossing LysMcre mice with Nrp-1 floxed mice. LysM-Cre-Nrp1^+/+, LysM-Cre-Nrp1^fl/fl and C57BL/6J WT mice were subjected to laser-induced CNV. CNV was evaluated ex vivo in flat mounted sclera-choroid-RPE cell complexes. qPCR served to analyze inflammatory profiles (Il-1β, Il-6 and Tnf-α) in choroids and retinas throughout disease (3, 7, 10, and 14 days post laser). An NRP-based trap was administered intravitreally and efficacy monitored for CNV.

Results : SEMA3A and VEGF-A were significantly increased in the vitreous of patients with neovascular AMD when compared to control patients with a non-vascular pathology.
CNV was decreased by 30% in LysM-Cre-Nrp1^fl/fl mice 14 days post laser compared to the control LysM-Cre-Nrp1^+/+ mice. Intrativitreal injection of an NRP-based recombinant trap reduced CNV by ~40%.

Conclusions : Our data identifies myeloid-resident NRP1 as a significant contributor to the pathological angiogenesis associated with CNV. Targeting NRP1 ligands may be a promising therapeutic strategy for neovascular diseases of the back of the eye.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.