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Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration
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نویسنده
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zhao l. ,li j. ,fu y. ,zhang m. ,wang b. ,ouellette j. ,shahi p.k. ,pattnaik b.r. ,watters j.j. ,wong w.t. ,guo l.-w.
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منبع
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journal of neuroinflammation - 2017 - دوره : 14 - شماره : 1
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چکیده
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Background: the bromodomain and extraterminal domain (bet) family proteins (bet2,bet3,and bet4) read (bind) histone acetylation marks via two distinct bromodomains (brom1 and brom2) facilitating transcriptional activation. these epigenetic readers play crucial roles in pathogenic processes such as inflammation. the role of bets in influencing the degenerative process in the retina is however unknown. methods: we employed the rd10 mouse model (pde6b rd10 mutation) of retinitis pigmentosa (rp) to examine the involvement of bet proteins in retinal neurodegeneration. results: inhibition of bet activity by intravitreal delivery of jq1,a bet-specific inhibitor binding both brom1 and brom2,ameliorated photoreceptor degeneration and improved electroretinographic function. rescue effects of jq1 were related to the suppression of retinal microglial activation in vivo,as determined by decreased immunostaining of activation markers (iba1,cd68,tspo) and messenger rna (mrna) levels of inflammatory cytokines in microglia purified from rd10 retinas. jq1 pre-treatment also suppressed microglial activation in vitro,decreasing microglial proliferation,migration,and mrna expression of inflammatory cytokines (tnfα,mcp-1,il-1β,il-6,and rantes). expression of bet2,but not bet3 and bet4,was significantly elevated during photoreceptor degeneration at postnatal day (pn)24 in retinas of rd10 mice relative to age-matched wild-type controls. sirna knockdown of bet2 but not bet4,and the inhibitor of brom2 (rvx208) but not of brom1 (olinone),decreased microglial activation. conclusions: these findings indicate that bet inhibition rescues photoreceptor degeneration likely via the suppression of microglial activation and implicates bet interference as a potential therapeutic strategy for the treatment of degenerative retinal diseases. © 2017 the author(s).
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کلیدواژه
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Bromodomain and extraterminal domain (BET) proteins; Epigenetic readers; JQ1; Microglial activation; Rd10 mice; Retinal degeneration
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آدرس
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university of wisconsin school of medicine and public health,department of surgery,5151 wisconsin institute for medical research,madison,wi 53705, United States, university of wisconsin school of medicine and public health,department of surgery,5151 wisconsin institute for medical research,madison,wi 53705,united states,the first hospital of china medical university,department of ophthalmology,shenyang,110001,china,the 3rd people's hospital of dalian,department of ophthalmology,dalian,116033, China, university of wisconsin school of medicine and public health,department of surgery,5151 wisconsin institute for medical research,madison,wi 53705,united states,shanghai jiao tong university school of medicine,shanghai key laboratory of psychotic disorders,shanghai mental health center,600 wanping nan road,shanghai,200030, China, university of wisconsin school of medicine and public health,department of surgery,5151 wisconsin institute for medical research,madison,wi 53705, United States, university of wisconsin school of medicine and public health,department of surgery,5151 wisconsin institute for medical research,madison,wi 53705, United States, university of wisconsin,department of comparative biosciences,madison,wi 53706, United States, university of wisconsin,department of pediatrics,madison,wi,united states,university of wisconsin,department of ophthalmology and visual sciences,madison,wi, United States, university of wisconsin,department of pediatrics,madison,wi,united states,university of wisconsin,mcpherson eye research institute,madison,wi 53705,united states,university of wisconsin,department of ophthalmology and visual sciences,madison,wi, United States, university of wisconsin,department of comparative biosciences,madison,wi 53706, United States, national institutes of health,unit on neuron-glia interactions in retinal disease,national eye institute,bethesda,md, United States, university of wisconsin school of medicine and public health,department of surgery,5151 wisconsin institute for medical research,madison,wi 53705,united states,university of wisconsin,mcpherson eye research institute,madison,wi 53705, United States
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Authors
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