Nogo-A-targeting antibody promotes visual recovery and inhibits neuroinflammation after retinal injury

Baya Mdzomba J, Joly S, Rodriguez L, Dirani A, Lassiaz P, Behar-Cohen F, Pernet V

Cell Death & Disease · 15 Aug 2022 · doi: 10.1038/s41419-020-2302-x

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Nogo-A is a potent myelin-associated inhibitor of neuronal growth and nervous system plasticity. It may be involved in many ocular diseases by preventing healing and recovery after physiological insults. This study shows that antibodies directed against Nogo-A promoted recovery after retinal injury. Baya Mdzomba et al monitor the visual acuity of the treated mice with our OptoDrum which provided a non-invasive readout of the injury and recovery, and enabled the researchers to get daily measurements of disease progression.

Abstract

N-Methyl-D-aspartate (NMDA)-induced neuronal cell death is involved in a large spectrum of diseases affecting the brain and the retina such as Alzheimer’s disease and diabetic retinopathy. Associated neurological impairments may result from the inhibition of neuronal plasticity by Nogo-A. The objective of the current study was to determine the contribution of Nogo-A to NMDA excitotoxicity in the mouse retina. We observed that Nogo-A is upregulated in the mouse vitreous during NMDA-induced inflammation. Intraocular injection of a function-blocking antibody specific to Nogo-A (11C7) was carried out 2 days after NMDA-induced injury. This treatment significantly enhanced visual function recovery in injured animals. Strikingly, the expression of potent pro-inflammatory molecules was downregulated by 11C7, among which TNFα was the most durably decreased cytokine in microglia/macrophages. Additional analyses suggest that TNFα downregulation may stem from cofilin inactivation in microglia/macrophages. 11C7 also limited gliosis presumably via P.Stat3 downregulation. Diabetic retinopathy was associated with increased levels of Nogo-A in the eyes of donors. In summary, our results reveal that Nogo-A-targeting antibody can stimulate visual recovery after retinal injury and that Nogo-A is a potent modulator of excitotoxicity-induced neuroinflammation. These data may be used to design treatments against inflammatory eye diseases.