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Ying Hu, Ming Yuan, Tian-lin Han, Jingtai Cao, Stanley Wiegand, George Yancopoulos; Genetic deletion of TLR4 increases retinal ganglion cell survival after optic nerve injury. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3253.
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Toll-like receptor 4 (TLR4) signaling has been shown to be involved in human glaucoma, which may be associated with innate and adaptive immune response (IOVS 2010;51(11):5697). In this study, we investigated the expression of TLR4 in the retina, and neuroprotective effect of TLR4 knockout (KO) after optic nerve (ON) injury.
Changes in the expression of TLR4 in the retina were assessed by TaqMan real-time PCR at different time points after ON crush. TLR4 KO mice were generated in which TLR4 was replaced with lacZ gene. Retinal ganglion cell (RGC) death was induced by ON crush or transection in age and gender matched WT and TLR4 KO mice. Animals were humanely euthanized 2 weeks after injury. The retinas were harvested, flat-mounted and stained for βIII-tubulin. The densities of RGCs were assessed and compared. One day before euthanization, animals received intravitreal injection of cholera toxin subunit β 488 to assess axon regeneration. The numbers of ganglion cell axons were quantified by examining the labeled axonal fibers in ON sections across the lesion site.
TLR4 mRNA levels in the retina were consistently upregulated after ON crush, from 12 hr to 14 days after injury. In retinas without ON injury, the average density of RGC in TLR4 KO mice was significantly lower than WT mice (p<0.001). Whereas in the injured eye, the average percentage of surviving RGCs in the TLR4 KO mice was significantly higher compared to WT mice after either ON crush (p<0.01) or complete transection (p<0.05). Genetic deletion of TLR4 had no effect on axon regeneration 2 week after ON crush.
Our findings demonstrate that TLR4 signaling is involved in RGC death following ON injury. Genetic deletion of TLR4 has a neuroprotective effect on RGC survival.
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