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

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.

Nogo-A is critical for pro-inflammatory gene regulation in myocytes and macrophages

“…We found that LPS-treated Nogo-KO BMDM expressed signi cantly decreased levels of IL-6, TNF-α, IL-1β, NF-κB, CXCL1, and CXCL2 compared with WT BMDM, whereas iNOS was not signi cantly downregulated in LPS-treated Nogo-KO BMDM compared with WT BMDM (Fig. 4c-i), as previously described [40,45]. These results suggest that Nogo-A may be involved in the activation of pro-in ammatory factors in LPS-treated WT BMDM.…”

“…1a). Recent research has noted that retinal excitotoxicity results in the upregulation of Nogo-A expression [40]. Our results suggest that only Nogo-A, but not Nogo-B or Nogo-C, is activated in injured muscle.…”

“…2d-f). A previous study showed that Nogo-A antibody treatment decreased the expression of in ammation-related genes [40]. These results suggest that Nogo-A upregulates CHOP, IL-6, and TNF-α expression.…”

“…We assessed differentiation-induced pro-in ammatory gene expression and found that Nogo-A knockdown led to signi cantly reduced levels of CHOP, IL-6, and TNF-α ( Fig. 3a), as JB Mdzomba et al showed that Nogo-A antibodies inhibit in ammation [40]. IF data also showed that Nogo-A silencing remarkably decreased Nogo-A and CHOP expression ( Fig.…”

Retinal microglia polarization in diabetic retinopathy

“…Nogo-A is a potent myelin-associated inhibitor for neuronal plasticity and axonal regeneration in the injured CNS (GrandPre et al, 2000). The study of Baya Mdzomba et al (2020) found that Nogo-A is upregulated in the retina of patients with DR. And the intravitreal injection of anti-Nogo-A antibody can improve visual function and reduce RMC-mediated inflammation after retinal injury. These data may be useful to develop new therapeutic approaches for DR or neurodegenerative diseases with an important inflammatory component.…”