Glaucoma is the leading cause of irreversible blindness worldwide.In the pathogen-esis of glaucoma,activated microglia can lead to retinal ganglion cells(RGCs)apoptosis and death,however,the molecular mechanisms remai...Glaucoma is the leading cause of irreversible blindness worldwide.In the pathogen-esis of glaucoma,activated microglia can lead to retinal ganglion cells(RGCs)apoptosis and death,however,the molecular mechanisms remain largely unknown.We demonstrate that phospholipid scramblase 1(PLSCR1)is a key regulator promoting RGCs apoptosis and their clearance by microglia.As evidenced in retinal progenitor cells and RGCs of the acute ocular hypertension(AOH)mouse model,overexpressed PLSCR1 induced its translocation from the nucleus to the cytoplasm and cytomembrane,as well as elevated phosphatidylserine exposure and reactive oxygen species generation with subsequent RGCs apoptosis and death.These damages were effectively attenuated by PLSCR1 inhibition.In the AOH model,PLSCR1 led to an increase in M1 type microglia activation and retinal neuroinflammation.Upregulation of PLSCR1 resulted in strongly elevated phagocytosis of apoptotic RGCs by activated microglia.Taken together,our study provides important insights linking activated microglia to RGCs death in the glaucoma pathogenesis and other RGC-related neurodegenerative diseases.展开更多
基金supported by The National Natural Science Foundation of China(No.81670894,81721003,81570862,82000915)The National Key Research and Development Program of China(No.2020YFA0112701)+5 种基金The Pearl River Talents Program-Local Innovative and Research Teams(No.2017BT01S138)The“100 talents plan”from Sun Yat-sen Universitythe Open Research Funds of the State Key Laboratory of Ophthalmology(No.2022KF04)The Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science(No.2017B030314025)The NSFC/Macao Science and Technology Development Fund(No.015/2017/AFJ to KZ)the Fundamental Research Funds for the Central Universities,Sun Yat-sen University(No.22qntd3902).
文摘Glaucoma is the leading cause of irreversible blindness worldwide.In the pathogen-esis of glaucoma,activated microglia can lead to retinal ganglion cells(RGCs)apoptosis and death,however,the molecular mechanisms remain largely unknown.We demonstrate that phospholipid scramblase 1(PLSCR1)is a key regulator promoting RGCs apoptosis and their clearance by microglia.As evidenced in retinal progenitor cells and RGCs of the acute ocular hypertension(AOH)mouse model,overexpressed PLSCR1 induced its translocation from the nucleus to the cytoplasm and cytomembrane,as well as elevated phosphatidylserine exposure and reactive oxygen species generation with subsequent RGCs apoptosis and death.These damages were effectively attenuated by PLSCR1 inhibition.In the AOH model,PLSCR1 led to an increase in M1 type microglia activation and retinal neuroinflammation.Upregulation of PLSCR1 resulted in strongly elevated phagocytosis of apoptotic RGCs by activated microglia.Taken together,our study provides important insights linking activated microglia to RGCs death in the glaucoma pathogenesis and other RGC-related neurodegenerative diseases.
