Dear Editor,Vascular endothelial growth factor-A(VEGFA,also known as VEGF)is a critical angiogenic factor that regulates the physiological and pathological blood vessel growth.1 Increased abundance of VEGF in the eye ...Dear Editor,Vascular endothelial growth factor-A(VEGFA,also known as VEGF)is a critical angiogenic factor that regulates the physiological and pathological blood vessel growth.1 Increased abundance of VEGF in the eye underlies many forms of aberrant ocular angiogenesis and resultant vision loss,including in neovascular age-related macular degeneration(nvAMD),proliferative diabetic retinopathy(PDR).展开更多
Nonfibrillar amyloid-βoligomers(AβOs)are a major component of drusen,the sub-retinal pigmented epithelium(RPE)extracellular deposits characteristic of age-related macular degeneration(AMD),a common cause of global b...Nonfibrillar amyloid-βoligomers(AβOs)are a major component of drusen,the sub-retinal pigmented epithelium(RPE)extracellular deposits characteristic of age-related macular degeneration(AMD),a common cause of global blindness.We report that AβOs induce RPE degeneration,a clinical hallmark of geographic atrophy(GA),a vision-threatening late stage of AMD that is currently untreatable.We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7,an upstream mediator of NLRP3 inflammasome activation,is required for AβO-induced RPE degeneration.Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors(NRTIs)and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration.These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.展开更多
基金J.A.has received support from the UVA Strategic Investment Fund,National Institutes of Health(NIH)grants(R01EY028027,R01EY029799,R01EY031039,R01AG082108)DuPont Guerry,III,Professorship,and a gift from Mr.and Mrs.Eli W.Tullis,S.B.W has received support from Annette Lightner Fund(Annette Lightner Research Award),B.D.G.has received support from NIH grants(R01EY028027,R01EY031039,R01EY032512,R01AG082108)BrightFocus Foundation Award M2020114,and the Owens Family Foundation.
文摘Dear Editor,Vascular endothelial growth factor-A(VEGFA,also known as VEGF)is a critical angiogenic factor that regulates the physiological and pathological blood vessel growth.1 Increased abundance of VEGF in the eye underlies many forms of aberrant ocular angiogenesis and resultant vision loss,including in neovascular age-related macular degeneration(nvAMD),proliferative diabetic retinopathy(PDR).
基金J.A.has received support from NIH grants(R01EY028027,R01EY29799,R01EY031039)DuPont Guerry,III,Professorship,a gift from Mr.and Mrs.Eli W.Tullis,and the University of Virginia Strategic Investment Fund+1 种基金B.D.G.has received support from NIH grants(R01EY028027 and R01EY031039)BrightFocus Foundation,and the Owens Family Foundation.
文摘Nonfibrillar amyloid-βoligomers(AβOs)are a major component of drusen,the sub-retinal pigmented epithelium(RPE)extracellular deposits characteristic of age-related macular degeneration(AMD),a common cause of global blindness.We report that AβOs induce RPE degeneration,a clinical hallmark of geographic atrophy(GA),a vision-threatening late stage of AMD that is currently untreatable.We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7,an upstream mediator of NLRP3 inflammasome activation,is required for AβO-induced RPE degeneration.Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors(NRTIs)and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration.These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.
