Cystoid edema, neovascularization and inflammatory processes in the murine Norrin-deficient retina

Susanne C Beck,Mathias W Seeliger,Thomas Langmann,Wolfgang Berger,Regine Mühlfriedel,Britta Seebauer,Katharina Dannhausen,Vithiyanjali Sothilingam,Marina Garcia Garrido,Hans-Peter Hammes,Marcus Karlstetter,Yuxi Feng

doi:10.1038/s41598-018-24476-y

Abstract

Mutations in the Norrin (NDP) gene cause severe developmental blood vessel defects in the retina leading to congenital blindness. In the retina of Ndph-knockout mice only the superficial capillary network develops. Here, a detailed characterization of this mouse model at late stages of the disease using in vivo retinal imaging revealed cystoid structures that closely resemble the ovoid cysts in the inner nuclear layer of the human retina with cystoid macular edema (CME). In human CME an involvement of Müller glia cells is hypothesized. In Ndph-knockout retinae we could demonstrate that activated Müller cells were located around and within these cystoid spaces. In addition, we observed extensive activation of retinal microglia and development of neovascularization. Furthermore, ex vivo analyses detected extravasation of monocytic cells suggesting a breakdown of the blood retina barrier. Thus, we could demonstrate that also in the developmental retinal vascular pathology present in the Ndph-knockout mouse inflammatory processes are active and may contribute to further retinal degeneration. This observation delivers a new perspective for curative treatments of retinal vasculopathies. Modulation of inflammatory responses might reduce the symptoms and improve visual acuity in these diseases.

Highlights

Norrin signalling is essential for correct vascular development
By investigating the long-term consequences of Norrin deficiency we observed a close interplay between the primary developmental defects and secondary alterations that affected the constituents of the retinal vasculature and resulted in the development of microaneurysm-like lesions with extensive vascular fenestration[9]
We detected a large number of cystoid lesions spread across the entire retina that closely resemble the retinal alterations of patients suffering from cystoid macular edema (CME)[10,11]

Summary

Introduction

Norrin signalling is essential for correct vascular development. Mutations in the NDP (Norrie disease pseudoglioma) gene that is encoding the Norrie protein[1] cause Norrie disease which is characterized by progressive deafness, mental retardation and congenital blindness[2]. By investigating the long-term consequences of Norrin deficiency we observed a close interplay between the primary developmental defects and secondary alterations that affected the constituents of the retinal vasculature and resulted in the development of microaneurysm-like lesions with extensive vascular fenestration[9]. Different factors like osmotic and hydrostatic forces, together with capillary permeability and tissue compliance ensure the fluid homeostasis of the retina. Any insult to this fine-tuned balance leads to cystic alterations that can be caused by either extra- or intracellular edema or both[10]. We observed neovascularization and widespread inflammatory processes involving Müller cell gliosis and microglia activation These observations give a new impact to the mouse model of Norrie disease. On the basis of our results we hypothesize that inflammation might be a common process that occurs in the chronic phase in many ocular diseases irrespective of the initial pathological process

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Conclusion