Abstract
Here, we have blocked the signaling pathway of tumor necrosis factor α (TNFα) in a mouse model of traumatic neuropathy using a small cell permeable molecule (R7050) that inhibits TNFα/TNF receptor 1 (TNFR1) complex internalization. Adult pigmented mice were subjected to intraorbital optic nerve crush (ONC). Animals received daily intraperitoneal injections of R7050, and/or a single intravitreal administration the day of the surgery. Some animals received a combinatorial treatment with R7050 (systemic or local) and a single intravitreal injection of brain derived neurotrophic factor (BDNF). As controls, untreated animals were used. Retinas were analyzed for RGC survival 5 and 14 days after the lesion i.e., during the quick and slow phase of axotomy-induced RGC death. qPCR analyses were done to verify that Tnfr1 and TNFα were up-regulated after ONC. At 5 days post-lesion, R7050 intravitreal or systemic treatment neuroprotected RGCs as much as BDNF alone. At 14 days, RGC rescue by systemic or intravitreal administration of R7050 was similar. At this time point, intravitreal treatment with BDNF was significantly better than intravitreal R7050. Combinatory treatment was not better than BDNF alone, although at both time points, the mean number of surviving RGCs was higher. In conclusion, antagonism of the extrinsic pathway of apoptosis rescues axotomized RGCs as it does the activation of survival pathways by BDNF. However, manipulation of both pathways at the same time, does not improve RGC survival.
Highlights
Introductiontumor necrosis factor α (TNFα) is a multi-functional cytokine that promotes inflammation and mediates cell death through the binding to TNF receptor 1 (TNFR1), a death receptor that triggers the extrinsic pathway of apoptosis (Lorz and Mehmet, 2009; Cabal-Hierro and Lazo, 2012; Sedger and McDermott, 2014)
TNF receptor 1 (TNFR1) is expressed in the inner nuclear layer (INL) and in the ganglion cell layer (GCL) (Figure 2A)
TNFR1 expression is observed in those retinal ganglion cell (RGC) with a lower signal of Brn3a, as we observed before for those RGCs expressing the cleaved form of caspase 3 (Sanchez-Migallon et al, 2016)
Summary
TNFα is a multi-functional cytokine that promotes inflammation and mediates cell death through the binding to TNF receptor 1 (TNFR1), a death receptor that triggers the extrinsic pathway of apoptosis (Lorz and Mehmet, 2009; Cabal-Hierro and Lazo, 2012; Sedger and McDermott, 2014). TNFα is expressed by microglial cells (Yuan and Neufeld, 2000; Roh et al, 2012), and TNFR1 by RGCs (Tezel et al, 2001; Agudo et al, 2008). TNFα induced cell death does not occur in healthy cells, but in stressed or metabolically imbalanced ones (reviewed in Sedger and McDermott, 2014). Complex I is membrane bound, and complex II is activated after being endocytosed and released from the cytoplasmic membrane (reviewed in CabalHierro and Lazo, 2012)
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