Intravitreal delivery of NMO-IgG causes primary retinal damage in the absence of optic nerve injury

Neuromyelitis Optica (NMO) is a neuroimmune disorder primarily driven by autoantibodies against aquaporin 4 (AQP4), known as NMO-IgG. Although the mechanisms underlying NMO-IgG-induced retinopathy are not fully understood, the high expression of AQP4 in retinal Müller cells suggests a direct interaction that may trigger inflammatory processes in the retina. Previous studies indicate that microglia play a critical role in mediating immune responses, leading to neuronal dysfunction.

The retinal dysfunction observed in NMO may primarily be linked to the activation of Müller cells by NMO-IgG, leading to increased C3 secretion, which in turn activates microglia. Therapeutic strategies targeting Müller cell-microglia interactions in NMO-IgG-induced retinopathy could be promising in addressing the underlying retinal pathology in this condition.

NMO-IgG obtained from clinical patients was administered via intravitreal injection to female C57BL/6 mice. Techniques such as optical coherence tomography (OCT), Flash Visual Evoked Potential (f-VEP), electroretinography (ERG), real-time fluorescence quantitative PCR (RT-qPCR), and immunofluorescence analyses were used to assess retinal changes. The potential for reversing retinopathy was explored by depleting microglial cells using the CSF1 receptor inhibitor PLX3397. Additionally, a Transwell co-culture system of MIO-M1 (Müller cells) and BV2 (microglia) cells was established to study their interactions.

Intravitreal injection of purified NMO-IgG in mouse models led to its deposition in the retina and downregulation of AQP4 in provided. Vascular leakage was observed, alongside retinal dysfunction characterized by thinning of the retinal nerve fiber layer (RNFL) and loss of retinal ganglion cells (RGCs). On day 7, C3 expression was upregulated in Müller cells, followed by microglial activation. Significant morphological changes in microglia were noted, with increased expression of iNOS and C1q, indicating substantial activation. Ablating microglia significantly mitigated NMO-IgG-induced injury to RGCs. In vitro, NMO-IgG-treated MIO-M1 cells secreted higher levels of C3, enhancing the activation and migration of BV2 cells compared to controls. Conclusions: The retinal dysfunction observed in NMO may primarily be linked to the activation of Müller cells by NMO-IgG, leading to increased C3 secretion, which in turn activates microglia. Therapeutic strategies targeting Müller cell-microglia interactions in NMO-IgG-induced retinopathy could be promising in addressing the underlying retinal pathology in this condition.