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*** co-receptor CD36 as a target in regulation of subretinal inflammation

Annals of Eye Science 2018年第1期 412-412页

作者： samy omri Sylvain Chemtob Department of Ophthalmology Hôpital Maisonneuve-Rosement Research CentreUniversitéde MontréalMontrealCanada

Subretinal inflammation plays a critical role in retinal degenerative *** activated macrophages have been shown to play a key role in the progression of retinopathies and specifically in age-related macular degeneration,little is known about the mechanisms involved in the loss of photoreceptors leading to vision *** our study on retinal damages induced by photo-oxidative stress,we have observed that CD36-deficient mice featured less subretinal macrophage accumulation with attenuated photoreceptor degeneration compared to wild-type(WT)*** with CD36-selective azapeptide ligand(labelled MPE-001)as modulator of the inflammatory environment of the retina reduced subretinal macrophage/activated microglia accumulation with preservation of photoreceptor layers and function assessed by ERG in WT,in a CD36-dependent *** azapeptide modulated the transcriptome of subretinal macrophage/activated microglia by reducing pro-inflammatory *** isolated macrophages,the CD36-selective azapeptide induced dissociation of the CD36-TLR2/6 heterodimer complex(using FRET)altering the TLR2 signaling pathway,thus decreasing NF-κB activation and inflammasome *** azapeptide also incurred cytoprotection against photoreceptor apoptosis elicited by activated *** findings suggest that the azapeptide as ligand of co-receptor CD36 decreases the inflammatory response by modulating CD36-TLR2/6 complex signaling pathway in macrophages,and suggests its potential application in the treatment of retinal degenerative diseases.

关键词： CD36 subretinal inflammation age-related macular degeneration

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*** of beta-adrenergic receptor in choroidal neovascularization

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Annals of Eye Science 2018年第1期 439-439页

作者： Houda Tahiri samy omri Isabelle Lahaie Sylvain Chemtob Research Center Hôpital Maisonneuve-Rosemont Universitéde MontréalMontréalQCCanada Research Center CHU Sainte-Justine Universitéde MontréalMontréalQCCanada Department of Pharmacology Universitéde MontréalMontréalQCCanada Department of Ophthalmology Universitéde MontréalMontréalQCCanada Department of Pediatrics Universitéde MontréalMontréalQCCanada

Background:We investigated the role of beta-adrenergic receptor(B-AR)on choroidal neovascularization(CNV)in an animal model of age-related macular degeneration in ***:The angiogenic effect of the B-AR was evaluated in retinal pigment epithelium(RPE)-choroid explants from C57Bl6 mice stimulated with propranolol or isoproterenol(10μM)(respectively antagonist and agonist of the B-AR)during 24 ***,a classic choroidal neovascularization(CNV)model induced by laser burn in C57Bl6 mice(8 weeks)was used to assess the anti-angiogenic effect of *** this experiment,mice were treated with intraperitoneal propranolol(6 mg/kg/d)or vehicle(saline solution)daily for 10 days,starting on day 4 after laser burn and until sacrifice(day 14).Immunostaining analysis on retinal flatmounts and cryosections were performed to determine the surface of CNV,the distribution of B-AR and the number and morphology of microglia/macrophages associated with *** explore if the antiangiogenic effect of propranolol involved the modulation of the inflammatory microenvironment associated with CNV,we used RPE primary cells,J774 macrophages cell line and polarized M1 and M2 bone marrow-derived macrophage(BMDM).Choroidal explants treated with conditioned media(CM)from J774 or polarized M1/M2 BMDM pre-treated with propranolol to confirm the anti-angiogenic effect of *** of angiogenic factors was evaluated by RT PCR and ***:The expression and distribution of the B-1,B-2 and B-3 adrenergic receptors were localized in the choroid and RPE *** stimulation of RPE-choroid explants with isoproterenol increased CNV compared to vehicle,while propranolol decreased *** vivo,propranolol inhibited significantly the levels of VEGF and CNV growth in laser burn model compared to the ***,the treatment with propranolol decremented the number of activated(amoeboid shape)microglia/macrophages but surprisingly,the number of non-activated microglia

关键词： Choroidal neovascularization(CNV) macrophages beta-adrenergic receptor(B-AR)

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***-standing choroidal thinning in oxygen-induced retinopathy

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Annals of Eye Science 2018年第1期 449-449页

作者： Tianwei Ellen Zhou Tang Zhu Houda Tahiri samy omri JoséCarlos Rivera Isabelle Lahaie Cheri Deal Stanley Nattel Sylvain Chemtob Department of Pharmacology McGill UniversityMontréalQCCanada Department of Pharmacology Universitéde MontréalMontréalQCCanada Research Center Hôpital Maisonneuve-Rosemont Universitéde MontréalMontréalQCCanada Research Center CHU Sainte-Justine Universitéde MontréalMontréalQCCanada Department of Pediatrics Universitéde MontréalMontréalQCCanada Department of Ophthalmology Universitéde MontréalMontréalQCCanada

Background:Retinopathy of prematurity(ROP),the most common cause of blindness in premature infants,has long been associated with pathologic retinal ***,recent studies reveal choroidal involution in adolescent patients formerly afflicted with *** have recently demonstrated that choroidal thinning occurs early in retinopathy and persists into *** retinal vessels,the damaged choroidal vasculature in ROP is incapably to ***,we investigated the molecular mechanism implicated in the lack of choroidal repair in ischemic ***:The oxygen-induced retinopathy(OIR)model was *** Sprague-Dawley(albino)or Long-Evans rats(pigmented)rats were placed under oxygen concentration which cycles at 50%±1%or 10%±1%every 24 hours(hr)from postnatal day(P)0 to *** P14,all rats were returned to room *** blotting and qPCR were used to quantify protein and RNA abundances,*** Dual-Luciferase®Reporter Assay System was used to confirm microRNA(miRNA)-mRNA ***:We detected a substantial oxidative stress in retinal pigment epithelium(RPE)and choroidal tissue,accompanied by a drastic reduction in insulin-like growth factor 1 receptor(IGF1R),a critical player in post-injury *** mechanism of decreasing IGF1R involves the over-activation of the p53 tumor suppressor that regulates miRNA let-7b,which subsequently silences Igf1r mRNA in the RPE/choroid complex of OIR *** reporter assay confirmed that let-7b directly targets Igf1r mRNA at its 3’untranslated region(UTR).Indeed,silencing p53 resulted in a decreased let-7b expression,and re-established IGF1R abundance that promoted choroidal ***:Together,this study sets forth new mechanistic notion by uncovering the novel p53/let-7b/IGF1R axis;timely intervention of this pathway facilitates healthy choroidal *** investigations on anti-angiogenic miRNAs can better our understanding

关键词： Choroid retinopathy of prematurity(ROP) p53 microRNA

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AB035. Lactate receptor GPR81 modulates epigenetic modification in the subretina

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Annals of Eye Science 2018年第1期 441-441页

作者： Xiaojuan Yang Raphael Rouget Tang Zhu Christiane Quiniou Shasha Lv Suna Jung Francois Duhamel Houda Tahiri samy omri Baraa Noueihed Xin Hou JoséCarlos Rivera Mathieu Nadeau-Vallée Pierre Lachapelle Sylvain Chemtob Department of Pharmacology McGill UniversityMontréalQCCanada Department of Pharmacology Universitéde MontréalMontréalQCCanada Research Center CHU Sainte-Justine Universitéde MontréalMontréalQCCanada Department of Ophthalmology and Neurology-Neurosurgery Montréal Children’s Hospital-Research InstituteMcGill UniversityMontréalQCCanada Research Center Hôpital Maisonneuve-Rosemont Universitéde MontréalMontréalQCCanada Department of Ophthalmology Universitéde MontréalMontréalQCCanada Department of Pediatrics Universitéde MontréalMontréalQCCanada

Background:Retinal pigment epithelium(RPE)is vital for the homeostasis of the subretina including photoreceptors and ***,our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in *** date,only one previous study has shown that activating GPR81 could enhance DNA repair by activating ***,we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81−/−***:GPR81−/−mice and wide type littermates were generated on a background of C57BL/6J *** thicknesses of their choroid were evaluated by ***,Q-PCR,western blot and choroid sprout assay were *** vitro,primary retinal pigment epithelium(pRPE)cells were isolated from mice,and cultured for ***:The thickness of choroid was reduced in GPR81−/−mice compared to GPR81+/+mice,suggesting that GPR81 is important for the integrity of *** the choroid sprout assay,lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their *** Q-PCR,most of the genes screened elevated their expression in GPR81−/−mice compared to WT mice,suggesting epigenetic modification may exist,which were confirmed by histone acetylation and HDACs activity ***:Taking together,the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the *** novel discovery sheds new light on the relationship between metabolism and epigenetic modification.

关键词： Subretina GPR81 epigenetic modification

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