Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in ...Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in neuroinflammation in the cerebrum.However,the effects of Homerla on NLRP3inflammasomes in retinal ischemia/reperfusion injury caused by elevated IOP remain unknown.In our study,animal models we re constructed using C57BL/6J and Homer1^(flox/-)/Homerla^(+/-)/Nestin-Cre^(+/-)mice with elevated IOP-induced retinal ischemia/repe rfusion injury.For in vitro expe riments,the oxygen-glucose deprivation/repe rfusion injury model was constructed with M uller cells.We found that Homerla ove rexpression amelio rated the decreases in retinal thickness and Muller cell viability after ischemia/reperfusion injury.Furthermore,Homerla knockdown promoted NF-κB P65^(Ser536)activation via caspase-8,NF-κB P65 nuclear translocation,NLRP3 inflammasome formation,and the production and processing of interleukin-1βand inte rleukin-18.The opposite results we re observed with Homerla ove rexpression.Finally,the combined administration of Homerla protein and JSH-23 significantly inhibited the reduction in retinal thickness in Homer1^(flox/-)Homer1a^(+/-)/Nestin-Cre^(+/-)mice and apoptosis in M uller cells after ischemia/reperfusion injury.Taken together,these studies demonstrate that Homer1a exerts protective effects on retinal tissue and M uller cells via the caspase-8/NF-KB P65/NLRP3 pathway after I/R injury.展开更多
Retinal injury after blunt ocular trauma may directly affect prognosis and lead to vision loss.To investigate the pathological changes and molecular mechanisms involved in retinal injury after blunt ocular trauma,we e...Retinal injury after blunt ocular trauma may directly affect prognosis and lead to vision loss.To investigate the pathological changes and molecular mechanisms involved in retinal injury after blunt ocular trauma,we established a weight drop injury model of blunt ocular trauma in male Beagle dogs.Hematoxylin-eosin staining,immunofluorescence staining,western blotting,and TUNEL assays were performed to investigate retinal injury within 14 days after blunt ocular trauma.Compared with the control group,the thicknesses of the inner and outer nuclear layers,as well as the number of retinal ganglion cells,gradually decreased within 14 days after injury.The number of bipolar cells in the inner nuclear layer began to decrease 1 day after injury,while the numbers of cholinergic and amacrine cells in the inner nuclear layer did not decrease until 7 days after injury.Moreover,retinal cell necroptosis increased with time after injury;it progressed from the ganglion cell layer to the outer nuclear layer.Visual electrophysiological findings indicated that visual impairment began on the first day after injury and worsened over time.Additionally,blunt ocular trauma induced nerve regeneration and Müller glial hyperplasia;it also resulted in the recruitment of microglia to the retina and polarization of those microglia to the M1 phenotype.These findings suggest that necroptosis plays an important role in exacerbating retinal injury after blunt ocular trauma via gliosis and neuroinflammation.Such a role has important implications for the development of therapeutic strategies.展开更多
基金supported by the Youth Development Project of Air Force Military Medical University,No.21 QNPY072Key Project of Shaanxi Provincial Natural Science Basic Research Program,No.2023-JC-ZD-48(both to FF)。
文摘Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in neuroinflammation in the cerebrum.However,the effects of Homerla on NLRP3inflammasomes in retinal ischemia/reperfusion injury caused by elevated IOP remain unknown.In our study,animal models we re constructed using C57BL/6J and Homer1^(flox/-)/Homerla^(+/-)/Nestin-Cre^(+/-)mice with elevated IOP-induced retinal ischemia/repe rfusion injury.For in vitro expe riments,the oxygen-glucose deprivation/repe rfusion injury model was constructed with M uller cells.We found that Homerla ove rexpression amelio rated the decreases in retinal thickness and Muller cell viability after ischemia/reperfusion injury.Furthermore,Homerla knockdown promoted NF-κB P65^(Ser536)activation via caspase-8,NF-κB P65 nuclear translocation,NLRP3 inflammasome formation,and the production and processing of interleukin-1βand inte rleukin-18.The opposite results we re observed with Homerla ove rexpression.Finally,the combined administration of Homerla protein and JSH-23 significantly inhibited the reduction in retinal thickness in Homer1^(flox/-)Homer1a^(+/-)/Nestin-Cre^(+/-)mice and apoptosis in M uller cells after ischemia/reperfusion injury.Taken together,these studies demonstrate that Homer1a exerts protective effects on retinal tissue and M uller cells via the caspase-8/NF-KB P65/NLRP3 pathway after I/R injury.
基金supported by the National Natural Science Foundation of China,No.81600738the Youth Development Project of Air Force Medical University,No.21QNPY072(both to FF)。
文摘Retinal injury after blunt ocular trauma may directly affect prognosis and lead to vision loss.To investigate the pathological changes and molecular mechanisms involved in retinal injury after blunt ocular trauma,we established a weight drop injury model of blunt ocular trauma in male Beagle dogs.Hematoxylin-eosin staining,immunofluorescence staining,western blotting,and TUNEL assays were performed to investigate retinal injury within 14 days after blunt ocular trauma.Compared with the control group,the thicknesses of the inner and outer nuclear layers,as well as the number of retinal ganglion cells,gradually decreased within 14 days after injury.The number of bipolar cells in the inner nuclear layer began to decrease 1 day after injury,while the numbers of cholinergic and amacrine cells in the inner nuclear layer did not decrease until 7 days after injury.Moreover,retinal cell necroptosis increased with time after injury;it progressed from the ganglion cell layer to the outer nuclear layer.Visual electrophysiological findings indicated that visual impairment began on the first day after injury and worsened over time.Additionally,blunt ocular trauma induced nerve regeneration and Müller glial hyperplasia;it also resulted in the recruitment of microglia to the retina and polarization of those microglia to the M1 phenotype.These findings suggest that necroptosis plays an important role in exacerbating retinal injury after blunt ocular trauma via gliosis and neuroinflammation.Such a role has important implications for the development of therapeutic strategies.
