Publications by authors named "Florian Sennlaub"

102 Publications

Reproducing diabetic retinopathy features using newly developed human induced-pluripotent stem cell-derived retinal Müller glial cells.

Glia 2021 Mar 8. Epub 2021 Mar 8.

Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France.

Muller glial cells (MGCs) are responsible for the homeostatic and metabolic support of the retina. Despite the importance of MGCs in retinal disorders, reliable and accessible human cell sources to be used to model MGC-associated diseases are lacking. Although primary human MGCs (pMGCs) can be purified from post-mortem retinal tissues, the donor scarcity limits their use. To overcome this problem, we developed a protocol to generate and bank human induced pluripotent stem cell-derived MGCs (hiMGCs). Using a transcriptome analysis, we showed that the three genetically independent hiMGCs generated were homogeneous and showed phenotypic characteristics and transcriptomic profile of pMGCs. These cells expressed key MGC markers, including Vimentin, CLU, DKK3, SOX9, SOX2, S100A16, ITGB1, and CD44 and could be cultured up to passage 8. Under our culture conditions, hiMGCs and pMGCs expressed low transcript levels of RLPB1, AQP4, KCNJ1, KCJN10, and SLC1A3. Using a disease modeling approach, we showed that hiMGCs could be used to model the features of diabetic retinopathy (DR)-associated dyslipidemia. Indeed, palmitate, a major free fatty acid with elevated plasma levels in diabetic patients, induced the expression of inflammatory cytokines found in the ocular fluid of DR patients such as CXCL8 (IL-8) and ANGPTL4. Moreover, the analysis of palmitate-treated hiMGC secretome showed an upregulation of proangiogenic factors strongly related to DR, including ANG2, Endoglin, IL-1β, CXCL8, MMP-9, PDGF-AA, and VEGF. Thus, hiMGCs could be an alternative to pMGCs and an extremely valuable tool to help to understand and model glial cell involvement in retinal disorders, including DR.
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http://dx.doi.org/10.1002/glia.23983DOI Listing
March 2021

VEGFR1 signaling in retinal angiogenesis and microinflammation.

Prog Retin Eye Res 2021 Feb 25:100954. Epub 2021 Feb 25.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany. Electronic address:

Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, -C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
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http://dx.doi.org/10.1016/j.preteyeres.2021.100954DOI Listing
February 2021

Modifications to the classical rat aortic ring model to allow vascular degeneration studies.

STAR Protoc 2021 Mar 21;2(1):100281. Epub 2021 Jan 21.

Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France.

The classical aortic ring model is well suited for deciphering pro-angiogenic processes. Here, we propose simple modifications of the standard protocol to study various anti-angiogenic processes from growth arrest to capillary degeneration. Aortic rings are cultured under basal conditions for 6 days to allow physiological vessel sprouting and then split into treatment groups to follow capillary growth or degeneration for an additional 2 days.
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http://dx.doi.org/10.1016/j.xpro.2020.100281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821348PMC
March 2021

Light-induced modifications of the outer retinal hyperreflective layers on spectral-domain optical coherence tomography in humans: an experimental study.

Acta Ophthalmol 2021 Jan 4. Epub 2021 Jan 4.

Department of Ophthalmology, Rothschild Foundation, Paris, France.

Purpose: Numerous small hyperreflective dots (HRDs) can be seen within the hyporeflective layer between the ellipsoid zone (EZ) and the interdigitation zone (IZ) on C-scan spectral-domain optical coherence tomography (SD-OCT) with a yet unknown variation under light conditions. The aim of this study was to explore light-induced SD-OCT changes in these HRDs.

Methods: The study subjects were randomly assigned to two groups: Group 1 experienced a dark adaptation protocol followed by intense retinal photobleaching, while Group 2, serving as the control group, was exposed to constant ambient light without any variation. The number of HRDs was automatically counted.

Results: Twenty healthy volunteers were prospectively included. The number of HRDs differed significantly over time (p = 0.0013). They decreased in Group 1 after dark adaptation and retinal photobleaching before returning to baseline levels 30 min later; conversely, they remained relatively constant in Group 2 throughout the study (p < 0.001). Light-skinned subjects had less HRD than dark-skinned subjects.

Conclusion: We observed light-induced modifications in the space between the EZ and the IZ. We hypothesize that the HRDs visible in this zone correspond to melanosomes that are mobilized during the light stimulation protocol. Larger studies are recommended to further evaluate and confirm light-induced SD-OCT changes under physiological and pathological conditions.
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http://dx.doi.org/10.1111/aos.14723DOI Listing
January 2021

Insulin inhibits inflammation-induced cone death in retinal detachment.

J Neuroinflammation 2020 Nov 26;17(1):358. Epub 2020 Nov 26.

Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France.

Background: Rhegmatogenous retinal detachment (RD) involving the macula is a major cause of visual impairment despite high surgical success rate, mainly because of cone death. RD causes the infiltration of activated immune cells, but it is not clear whether and how infiltrating inflammatory cells contribute to cone cell loss.

Methods: Vitreous samples from patients with RD and from control patients with macular hole were analyzed to characterize the inflammatory response to RD. A mouse model of RD and retinal explants culture were then used to explore the mechanisms leading to cone death.

Results: Analysis of vitreous samples confirms that RD induces a marked inflammatory response with increased cytokine and chemokine expression in humans, which is closely mimicked by experimental murine RD. In this model, we corroborate that myeloid cells and T-lymphocytes contribute to cone loss, as the inhibition of their accumulation by Thrombospondin 1 (TSP1) increased cone survival. Using monocyte/retinal co-cultures and TSP1 treatment in RD, we demonstrate that immune cell infiltration downregulates rod-derived cone viability factor (RdCVF), which physiologically regulates glucose uptake in cones. Insulin and the insulin sensitizers rosiglitazone and metformin prevent in part the RD-induced cone loss in vivo, despite the persistence of inflammation CONCLUSION: Our results describe a new mechanism by which inflammation induces cone death in RD, likely through cone starvation due to the downregulation of RdCVF that could be reversed by insulin. Therapeutic inhibition of inflammation and stimulation of glucose availability in cones by insulin signaling might prevent RD-associated cone death until the RD can be surgically repaired and improve visual outcome after RD.

Trial Registration: ClinicalTrials.gov NCT03318588.
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http://dx.doi.org/10.1186/s12974-020-02039-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694924PMC
November 2020

[On the inflammatory origins of AMD].

Med Sci (Paris) 2020 Oct 7;36(10):886-892. Epub 2020 Oct 7.

Sorbonne Université, Inserm, CNRS, Institut de la vision, 17 rue Moreau, F-75012 Paris, France.

Age-related macular degeneration (AMD) is a complex, highly heritable, multifactorial disease caused by the interplay of age and genetic and environmental risk factors. No treatment has yet been found to treat the slowly progressing atrophic form of AMD. All forms of AMD are invariably associated with an accumulation of mononuclear phagocytes (MP) in the subretinal space, a family of cells that include inflammatory and resident macrophages. We here present an overview of the inflammatory process occurring in AMD and discuss the origin of MPs and the consequences of their accumulation in the subretinal space. Finally, we will review the role played by the established risk factors for AMD to promote the switch from beneficial inflammation in early stage to a deleterious inflammation in the advanced stage of the disease.
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http://dx.doi.org/10.1051/medsci/2020159DOI Listing
October 2020

Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy.

Science 2020 08;369(6506)

Departments of Ophthalmology and

In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.
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http://dx.doi.org/10.1126/science.aay5356DOI Listing
August 2020

The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination.

Immunity 2020 08;53(2):429-441.e8

Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France. Electronic address:

A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility. We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD. HTRA1 induced the persistence of monocytes in the subretinal space and exacerbated pathogenic inflammation by hydrolyzing thrombospondin 1 (TSP1), which separated the two CD47-binding sites within TSP1 that are necessary for efficient CD47 activation. This HTRA1-induced inhibition of CD47 signaling induced the expression of pro-inflammatory osteopontin (OPN). OPN expression increased in early monocyte-derived macrophages in 10q26 risk carriers. In models of subretinal inflammation and AMD, OPN deletion or pharmacological inhibition reversed HTRA1-induced pathogenic MP persistence. Our findings argue for the therapeutic potential of CD47 agonists and OPN inhibitors for the treatment of AMD.
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http://dx.doi.org/10.1016/j.immuni.2020.07.021DOI Listing
August 2020

Deletion of the myeloid endothelin-B receptor confers long-term protection from angiotensin II-mediated kidney, eye and vessel injury.

Kidney Int 2020 11 20;98(5):1193-1209. Epub 2020 Jun 20.

Paris Cardiovascular Research Centre-PARCC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France; University/BHF Centre of Research Excellence, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK. Electronic address:

The endothelin system may be an important player in hypertensive end-organ injury as endothelin-1 increases blood pressure and is pro-inflammatory. The immune system is emerging as an important regulator of blood pressure and we have shown that the early hypertensive response to angiotensin-II infusion was amplified in mice deficient of myeloid endothelin-B (ET) receptors (LysM-CreEdnrblox/lox). Hypothesizing that these mice would display enhanced organ injury, we gave angiotensin-II to LysM-CreEdnrblox/lox and littermate controls (Ednrblox/lox) for six weeks. Unexpectedly, LysM-CreEdnrblox/lox mice were significantly protected from organ injury, with less proteinuria, glomerulosclerosis and inflammation of the kidney compared to controls. In the eye, LysM-CreEdnrblox/lox mice had fewer retinal hemorrhages, less microglial activation and less vessel rarefaction. Cardiac remodeling and dysfunction were similar in both groups at week six but LysM-CreEdnrblox/lox mice had better endothelial function. Although blood pressure was initially higher in LysM-CreEdnrblox/lox mice, this was not sustained. A natriuretic switch at about two weeks, due to enhanced ET signaling in the kidney, induced a hypertensive reversal. By week six, blood pressure was lower in LysM-CreEdnrblox/lox mice than in controls. At six weeks, macrophages from LysM-CreEdnrblox/lox mice were more anti-inflammatory and had greater phagocytic ability compared to the macrophages of Ednrblox/lox mice. Thus, myeloid cell ET receptor signaling drives this injury both through amplifying hypertension and by inflammatory polarization of macrophages.
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http://dx.doi.org/10.1016/j.kint.2020.05.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652550PMC
November 2020

Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis.

Immunity 2020 09 19;53(3):627-640.e5. Epub 2020 Jun 19.

Institut National de la Santé et de la Recherche Médicale (Inserm, UMR_S 1166), Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France. Electronic address:

Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C monocytes during NASH, underlying impaired KC self-renewal. Monocyte-derived KCs (MoKCs) gradually seeded the KC pool as disease progressed in a response to embryo-derived KC (EmKC) death. Those MoKCs were partly immature and exhibited a pro-inflammatory status compared to EmKCs. Yet, they engrafted the KC pool for the long term as they remained following disease regression while acquiring mature EmKC markers. While KCs as a whole favored hepatic triglyceride storage during NASH, EmKCs promoted it more efficiently than MoKCs, and the latter exacerbated liver damage, highlighting functional differences among KCs with different origins. Overall, our data reveal that KC homeostasis is impaired during NASH, altering the liver response to lipids, as well as KC ontogeny.
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http://dx.doi.org/10.1016/j.immuni.2020.06.003DOI Listing
September 2020

Microglia versus Monocytes: Distinct Roles in Degenerative Diseases of the Retina.

Trends Neurosci 2020 06 17;43(6):433-449. Epub 2020 Apr 17.

Department of Ophthalmology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University,Durham, NC 27710, USA. Electronic address:

Unlike in the healthy mammalian retina, macrophages in retinal degenerative states are not solely comprised of microglia but may include monocyte-derived recruits. Recent studies have applied transgenics, lineage-tracing, and transcriptomics to help decipher the distinct roles of these two cell types in the diseasesettings of inherited retinal degenerations and age-related macular degeneration.Literature discussed here focuses on the ectopic presence of both macrophage types in the extracellular site surrounding the outer aspect ofphotoreceptor cells (i.e.,the subretinal space), which is crucially involved in the pathobiology. From these studies we propose a working model in which perturbed photoreceptor states cause microglial dominant migration to the subretinal space as a protective response, whereas the abundant presence ofmonocyte-derived cells there instead drives and accelerates pathology. The latter, we propose, is underpinned by specific genetic and nongenetic determinants that lead to a maladaptive macrophage state.
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http://dx.doi.org/10.1016/j.tins.2020.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556353PMC
June 2020

CD36 Deficiency Inhibits Retinal Inflammation and Retinal Degeneration in Knockout Mice.

Front Immunol 2019 8;10:3032. Epub 2020 Jan 8.

Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France.

CD36, a member of the class B scavenger receptor family, participates in Toll-like receptor signaling on mononuclear phagocytes (MP) and can promote sterile pathogenic inflammation. We here analyzed the effect of CD36 deficiency on retinal inflammation and photoreceptor degeneration, the hallmarks of age-related macular degeneration (AMD), that characterize mice. We analyzed subretinal MP accumulation, and cone- and rod-degeneration in light-challenged and aged, CD36 competent or deficient, hyper-inflammatory mice, using histology and immune-stained retinal flatmounts. Monocytes (Mo) were subretinally adoptively transferred to evaluate their elimination rate from the subretinal space and Interleukin 6 (IL-6) secretion from cultured Mo-derived cells (MdCs) of the different mouse strains were analyzed. CD36 deficient mice were protected against age- and light-induced subretinal inflammation and associated cone and rod degeneration. CD36 deficiency in MPs inhibited their prolonged survival in the immune-suppressive subretinal space and reduced the exaggerated IL-6 secretion observed in MPs that we previously showed leads to increased subretinal MP survival. deficiency significantly protected hyperinflammatory mice against subretinal MP accumulation and associated photoreceptor degeneration. The observed CD36-dependent induction of pro-inflammatory IL-6 might be at least partially responsible for the prolonged MP survival in the immune-suppressive environment and its pathological consequences on photoreceptor homeostasis.
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http://dx.doi.org/10.3389/fimmu.2019.03032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960398PMC
November 2020

IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis.

J Neuroinflammation 2020 Jan 3;17(1). Epub 2020 Jan 3.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France.

Background: Age-related macular degeneration is characterized by the accumulation of subretinal macrophages and the degeneration of cones, but mainly of rods. We have previously shown that Mononuclear Phagocytes-derived IL-1β induces rod photoreceptor cell death during experimental subretinal inflammation and in retinal explants exposed to IL-1β but the mechanism is unknown.

Methods: Retinal explants were culture in the presence of human monocytes or IL-1β and photoreceptor cell survival was analyzed by TUNEL labeling. Glutamate concentration and transcription levels of gene involved in the homeostasis of glutamate were analyzed in cell fractions of explant cultured or not in the presence of IL-1β. Glutamate receptor antagonists were evaluated for their ability to reduce photoreceptor cell death in the presence of IL1-β or monocytes.

Results: We here show that IL-1β does not induce death in isolated photoreceptors, suggesting an indirect effect. We demonstrate that IL-1β leads to glutamate-induced rod photoreceptor cell death as it increases the extracellular glutamate concentrations in the retina through the inhibition of its conversion to glutamine in Müller cells, increased release from Müller cells, and diminished reuptake. The inhibition of non-NMDA receptors completely and efficiently prevented rod apoptosis in retinal explants cultured in the presence of IL-1β or, more importantly, in vivo, in a model of subretinal inflammation.

Conclusions: Our study emphasizes the importance of inflammation in the deregulation of glutamate homeostasis and provides a comprehensive mechanism of action for IL-1β-induced rod degeneration.
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http://dx.doi.org/10.1186/s12974-019-1655-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942287PMC
January 2020

Evidence of the involvement of dystrophin Dp71 in corneal angiogenesis.

Mol Vis 2019 14;25:714-721. Epub 2019 Nov 14.

Institut De La Vision, Sorbonne Universités, UPMC Univ Paris 06, UMR_S, 968, Paris, France, Paris, France.

Purpose: The aim of this study was to define the role of dystrophin Dp71 in corneal angiogenesis.

Methods: Inflammation-induced corneal neovascularization experiments were performed in -null mice and C57BL/6J wild-type mice.

Results: The corneal neovascular area covered by neovascularization was larger in the injured corneas of the -null mice compared to the corneas of the wild-type mice: 40.72% versus 26.33%, respectively (p<0.005). Moreover, increased angiogenesis was associated with a high expression of vascular endothelial growth factor (VEGF). Similarly, aortic ring assays showed a significant enhancement of the neovascular area.

Conclusions: These results suggest that dystrophin Dp71 could play an important role as a negative regulator of corneal angiogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857772PMC
June 2020

Immunometabolic modulation of retinal inflammation by CD36 ligand.

Sci Rep 2019 09 9;9(1):12903. Epub 2019 Sep 9.

Faculty of Pharmacy, Université de Montréal, Montreal, Canada.

In subretinal inflammation, activated mononuclear phagocytes (MP) play a key role in the progression of retinopathies. Little is known about the mechanism involved in the loss of photoreceptors leading to vision impairment. Studying retinal damage induced by photo-oxidative stress, we observed that cluster of differentiation 36 (CD36)-deficient mice featured less subretinal MP accumulation and attenuated photoreceptor degeneration. Moreover, treatment with a CD36-selective azapeptide ligand (MPE-001) reduced subretinal activated MP accumulation in wild type mice and preserved photoreceptor layers and function as assessed by electroretinography in a CD36-dependent manner. The azapeptide modulated the transcriptome of subretinal activated MP by reducing pro-inflammatory markers. In isolated MP, MPE-001 induced dissociation of the CD36-Toll-like receptor 2 (TLR2) oligomeric complex, decreasing nuclear factor-kappa B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. In addition, MPE-001 caused an aerobic metabolic shift in activated MP, involving peroxisome proliferator-activated receptor-γ (PPAR-γ) activation, which in turn mitigated inflammation. Accordingly, PPAR-γ inhibition blocked the cytoprotective effect of MPE-001 on photoreceptor apoptosis elicited by activated MP. By altering activated MP metabolism, MPE-001 decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury characteristic of various vision-threatening retinal disorders.
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http://dx.doi.org/10.1038/s41598-019-49472-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733801PMC
September 2019

Prevalence and risk factors for outer retinal layer damage after macula-off retinal detachment.

Br J Ophthalmol 2020 05 28;104(5):660-665. Epub 2019 Aug 28.

Department of Ophthalmology, University Hospital Centre Nancy, Nancy, France

Purpose: To report the prevalence of outer retinal layer (ORL) damage after macula-off rhegmatogenous retinal detachment (RRD) surgery and to determine its associated preoperative risk factors.

Methods: 253 eyes successfully operated for macula-off RRD were included in the study. The integrity of the external limiting membrane (ELM), ellipsoid zone (EZ) and cone interdigitation zone (CIZ) of the photoreceptors was assessed at 1 month and 6 months using spectral-domain optical coherence tomography. Risk factors were analysed using univariate and multivariate logistic regression. The correlation between ORL integrity and visual outcomes was also evaluated.

Results: CIZ, EZ and ELM defects were found in, respectively, 198 (93.4%) eyes, 100 (47.2%) eyes, 64 (30.2%) eyes at 1 month and in 160 (63.2%) eyes, 44 (17.4%) eyes and 18 (7.1%) eyes at 6 months. In multivariate analysis, duration of macular detachment was the only factor associated with ORL damage at 6 months (p=0.007). Best-corrected visual acuity significantly improved from 0.5±0.3 at 1 month to 0.3±0.3 logarithm of minimal angle of resolution at 6 months (p<0.001) and was strongly correlated with the number of affected bands (p<0.001).

Conclusion: Prevalence of outer retinal band defects substantially decreased through the study period, confirming the ability of photoreceptors to recover over time. However, shorter interval to surgery and better visual outcomes were significantly associated with fewer defects within the ORL at 6 months. These findings suggest that earlier surgery may limit RRD-associated photoreceptor degeneration and improve the patient's visual prognosis.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314236DOI Listing
May 2020

Mo-derived perivascular macrophage recruitment protects against endothelial cell death in retinal vein occlusion.

J Neuroinflammation 2019 Jul 27;16(1):157. Epub 2019 Jul 27.

INSERM, CNRS, Institut de la Vision, 17 rue Moreau, Sorbonne Université, UPMC Univ Paris 06, F-75012, Paris, France.

Background: To decipher the role of monocyte-derived macrophages (Mφs) in vascular remodeling of the occluded vein following experimental branch retinal vein occlusion (BRVO).

Methods: The inflammation induced by laser-induced BRVO on mice retina was evaluated at different time points by RT-PCR looking at inflammatory markers mRNA level expression, Icam-1, Cd11b, F4/80, Ccl2, and Ccr2 and by quantification of Iba1-positive macrophage (Mφ) density on Iba1-stained retinal flatmount. Repeated intraperitoneal EdU injection combined with liposome clodronate-induced monocyte (Mo) depletion in wildtype mice was used to differentiate Mo-derived Mφs from resident Mφs. Liposome clodronate Mo-depleted wildtype mice and Ccr2-deficient mice were used to evaluate the role of all CCR2 and CCR2 Mo-derived Mφs on EC apoptosis in the occluded vein.

Results: cd11b, ICAM-1, F4/80, Ccl2, and Ccr2 mRNA expression were increased 1, 3, and 7 days after vein occlusion. The number of parenchymal (parMφs) and perivascular (vasMφs) macrophages was increased 3 and 7 days after BRVO. The systemic depletion of all circulating Mos decreased significantly the BRVO-induced parMφs and vasMφs macrophage accumulation, while the deletion of CCR2-inflammatory Mo only diminished the accumulation of parMφs, but not vasMφs. Finally, apoptotic ECs of the vein were more numerous in fully depleted, liposome clodronate-treated mice, than in Ccr2 mice that only lack the recruitment of CCR2 inflammatory Mos.

Conclusions: BRVO triggers the recruitment of blood-derived parMφs and vasMφs. Interestingly, vasMφs accumulation was independent of CCR2. The observation that the inhibition of the recruitment of all infiltrating Mφs increases the vein EC apoptosis, while CCR2 deficiency does not, demonstrates that CCR2 Mo-derived vasMφs protect the ECs against apoptosis in the occluded vein.
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http://dx.doi.org/10.1186/s12974-019-1547-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660930PMC
July 2019

Is Retinal Metabolic Dysfunction at the Center of the Pathogenesis of Age-related Macular Degeneration?

Int J Mol Sci 2019 Feb 11;20(3). Epub 2019 Feb 11.

. Department of Therapeutics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France.

The retinal pigment epithelium (RPE) forms the outer blood⁻retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized via OXPHOS. Excess lactate in the RPE is transported across the basolateral membrane to the choroid. The uptake of glucose by cone photoreceptor cells is enhanced by rod-derived cone viability factor (RdCVF) secreted by rods and by insulin signaling. Together, the three cells act as symbiotes: the RPE supplies the glucose from the choroidal circulation to the photoreceptors, the rods help the cones, and both produce lactate to feed the RPE. In age-related macular degeneration this delicate ménage à trois is disturbed by the chronic infiltration of inflammatory macrophages. These immune cells also rely on aerobic glycolysis and compete for glucose and produce lactate. We here review the glucose metabolism in the homeostasis of the outer retina and in macrophages and hypothesize what happens when the metabolism of photoreceptors and the RPE is disturbed by chronic inflammation.
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http://dx.doi.org/10.3390/ijms20030762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387069PMC
February 2019

Adaptive optics ophthalmoscopy: Application to age-related macular degeneration and vascular diseases.

Prog Retin Eye Res 2018 09 17;66:1-16. Epub 2018 Jul 17.

Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS Clinical Investigation Center, 1423, Paris, France.

Adaptive optics (AO)-enhanced en face retinal imaging, termed here AO ophthalmoscopy (AOO) has reached a level of robustness which fuels its increasing use in research and clinical centers. Here we will review the contribution of clinical AOO to the understanding and monitoring of 1) age-related macular degeneration and 2) vascular diseases. The main contributions of AOO to the phenotyping of AMD are a better identification of drusen, a better delineation of the limits of atrophy, and the identification of novel features such as punctate hyperreflectivity and mobile melanin-containing clumps. Characterization of progression of atrophy is facilitated by time-lapse imaging. In vessels, AOO enables the observation and measurement of parietal structures and the observation of microscopic pathological features such as small hemorrhages and inflammatory cell accumulations.
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http://dx.doi.org/10.1016/j.preteyeres.2018.07.001DOI Listing
September 2018

Neuropilin-1 expression in adipose tissue macrophages protects against obesity and metabolic syndrome.

Sci Immunol 2018 03;3(21)

Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec H1T 2M4, Canada.

Obesity gives rise to metabolic complications by mechanisms that are poorly understood. Although chronic inflammatory signaling in adipose tissue is typically associated with metabolic deficiencies linked to excessive weight gain, we identified a subset of neuropilin-1 (NRP1)-expressing myeloid cells that accumulate in adipose tissue and protect against obesity and metabolic syndrome. Ablation of NRP1 in macrophages compromised lipid uptake in these cells, which reduced substrates for fatty acid β-oxidation and shifted energy metabolism of these macrophages toward a more inflammatory glycolytic metabolism. Conditional deletion of NRP1 in LysM Cre-expressing cells leads to inadequate adipose vascularization, accelerated weight gain, and reduced insulin sensitivity even independent of weight gain. Transfer of NRP1 hematopoietic cells improved glucose homeostasis, resulting in the reversal of a prediabetic phenotype. Our findings suggest a pivotal role for adipose tissue-resident NRP1-expressing macrophages in driving healthy weight gain and maintaining glucose tolerance.
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http://dx.doi.org/10.1126/sciimmunol.aan4626DOI Listing
March 2018

Chronic exposure to tumor necrosis factor alpha induces retinal pigment epithelium cell dedifferentiation.

J Neuroinflammation 2018 Mar 16;15(1):85. Epub 2018 Mar 16.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012, Paris, France.

Background: The retinal pigment epithelium (RPE) is a monolayer of pigmented cells with important barrier and immuno-suppressive functions in the eye. We have previously shown that acute stimulation of RPE cells by tumor necrosis factor alpha (TNFα) downregulates the expression of OTX2 (Orthodenticle homeobox 2) and dependent RPE genes. We here investigated the long-term effects of TNFα on RPE cell morphology and key functions in vitro.

Methods: Primary porcine RPE cells were exposed to TNFα (at 0.8, 4, or 20 ng/ml per day) for 10 days. RPE cell morphology, phagocytosis, barrier- and immunosuppressive-functions were assessed.

Results: Chronic (10 days) exposure of primary RPE cells to TNFα increases RPE cell size and polynucleation, decreases visual cycle gene expression, impedes RPE tight-junction organization and transepithelial resistance, and decreases the immunosuppressive capacities of the RPE. TNFα-induced morphological- and transepithelial-resistance changes were prevented by concomitant Transforming Growth Factor β inhibition.

Conclusions: Our results indicate that chronic TNFα-exposure is sufficient to alter RPE morphology and impede cardinal features that define the differentiated state of RPE cells with striking similarities to the alterations that are observed with age in neurodegenerative diseases such as age-related macular degeneration.
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http://dx.doi.org/10.1186/s12974-018-1106-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857126PMC
March 2018

The Oxygen Paradox, the French Paradox, and age-related diseases.

Geroscience 2017 12 21;39(5-6):499-550. Epub 2017 Dec 21.

Laboratoire de Signalisation et Physiopathologie Cardiovasculaire-Inserm UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry, Paris, France.

A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen "a toxic environmental poison" could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.g., cheese and paté) will result in an early death from cardiovascular diseases (Renaud and de Lorgeril Lancet 339(8808):1523-6, 1992; Catalgol et al. Front Pharmacol 3:141, 2012; Eisenberg et al. Nat Med 22(12):1428-1438, 2016)?: the so-called, French Paradox. Doubtless, the truth is not a duality and epistemological bias probably generates apparently self-contradictory conclusions. Perhaps nowhere in biology are there so many apparently contradictory views, and even experimental results, affecting human physiology and pathology as in the fields of free radicals and oxidative stress, antioxidants, foods and drinks, and dietary recommendations; this is particularly true when issues such as disease-susceptibility or avoidance, "healthspan," "lifespan," and ageing are involved. Consider, for example, the apparently paradoxical observation that treatment with low doses of a substance that is toxic at high concentrations may actually induce transient adaptations that protect against a subsequent exposure to the same (or similar) toxin. This particular paradox is now mechanistically explained as "Adaptive Homeostasis" (Davies Mol Asp Med 49:1-7, 2016; Pomatto et al. 2017a; Lomeli et al. Clin Sci (Lond) 131(21):2573-2599, 2017; Pomatto and Davies 2017); the non-damaging process by which an apparent toxicant can activate biological signal transduction pathways to increase expression of protective genes, by mechanisms that are completely different from those by which the same agent induces toxicity at high concentrations. In this review, we explore the influences and effects of paradoxes such as the Oxygen Paradox and the French Paradox on the etiology, progression, and outcomes of many of the major human age-related diseases, as well as the basic biological phenomenon of ageing itself.
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http://dx.doi.org/10.1007/s11357-017-0002-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745211PMC
December 2017

The 3D Retinal Capillary Circulation in Pigs Reveals a Predominant Serial Organization.

Invest Ophthalmol Vis Sci 2017 11;58(13):5754-5763

Institut de la Vision, Sorbonne Universiteés, UPMC University Paris 06, INSERM, CNRS, Paris, France.

Purpose: To establish a model of the retinal capillary circulation in pigs, which in many aspects is close to the human retina.

Methods: Using high density confocal microscopy image stacks of immunolabeled porcine retinal whole mounts, microvessels close to the optic nerve head were traced in three dimensions. The direction of flow of individual capillaries was deduced from their arteriolar and/or venous connections.

Results: From major arteries, second-order arteries traversed the nerve fiber layer and resolved exclusively into the superficial vascular plexus (SVP), which dichotomized the blood flow between radial peripapillary capillaries (RPCs) on one side and the intermediate (IVP) and deep vascular plexus (DVP) on the other. Each RPC was supplied by one or several capillaries from the SVP and drained to the IVP or DVP. The DVP was a mosaic of approximately 300 to 600 μm wide anastomotic watersheds, each drained by one or two venules connected to major veins. A presumptive direction of flow could be determined for >90% of capillaries. These results suggest a model of the capillary circulation in which the three microvessel layers are serially organized with RPCs are in parallel between the SVP and IVP or DVP.

Conclusions: In the peripapillary retina of pigs, microvascular layers have a serial arrangement, with RPCs emerging from the SVP and draining to the IVP or DVP; hence, connected in parallel of this scheme. The bulk of flow, therefore, traverses the SVP and DVP successively. This organization contributes to the higher oxygen saturation in the SVP and RPCs than in the DVP. Physiopathologic implications of this model regarding retinal diseases are discussed.
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http://dx.doi.org/10.1167/iovs.17-22097DOI Listing
November 2017

On phagocytes and macular degeneration.

Prog Retin Eye Res 2017 Nov 7;61:98-128. Epub 2017 Jun 7.

Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012, Paris, France. Electronic address:

Age related macular degeneration (AMD) is a complex multifactorial disease caused by the interplay of age and genetic and environmental risk factors. A common feature observed in early and both forms of late AMD is the breakdown of the physiologically immunosuppressive subretinal environment and the protracted accumulation of mononuclear phagocytes (MP). We here discuss the origin and nature of subretinal MPs, the mechanisms that lead to their accumulation, the inflammatory mediators they produce as well as the consequences of their chronic presence on photoreceptors, retinal pigment epithelium and choroid. Recent advances highlight how both genetic and environmental risk factors directly promote subretinal inflammation and tip the balance from a beneficial inflammation that helps control debris accumulation to detrimental chronic inflammation and destructive late AMD. Finally, we discuss how changes in life style or pharmacological intervention can help to break the vicious cycle of inflammation and degeneration, restore the immunosuppressive properties of the subretinal space, and reestablish homeostasis.
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http://dx.doi.org/10.1016/j.preteyeres.2017.06.002DOI Listing
November 2017

Comprehensive analysis of mouse retinal mononuclear phagocytes.

Nat Protoc 2017 Jun 4;12(6):1136-1150. Epub 2017 May 4.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.

The innate immune system is activated in a number of degenerative and inflammatory retinal disorders such as age-related macular degeneration (AMD). Retinal microglia, choroidal macrophages, and recruited monocytes, collectively termed 'retinal mononuclear phagocytes', are critical determinants of ocular disease outcome. Many publications have described the presence of these cells in mouse models for retinal disease; however, only limited aspects of their behavior have been uncovered, and these have only been uncovered using a single detection method. The workflow presented here describes a comprehensive analysis strategy that allows characterization of retinal mononuclear phagocytes in vivo and in situ. We present standardized working steps for scanning laser ophthalmoscopy of microglia from MacGreen reporter mice (mice expressing the macrophage colony-stimulating factor receptor GFP transgene throughout the mononuclear phagocyte system), quantitative analysis of Iba1-stained retinal sections and flat mounts, CD11b-based retinal flow cytometry, and qRT-PCR analysis of key microglia markers. The protocol can be completed within 3 d, and we present data from retinas treated with laser-induced choroidal neovascularization (CNV), bright white-light exposure, and Fam161a-associated inherited retinal degeneration. The assays can be applied to any of the existing mouse models for retinal disorders and may be valuable for documenting immune responses in studies for immunomodulatory therapies.
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http://dx.doi.org/10.1038/nprot.2017.032DOI Listing
June 2017

Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation.

Immunity 2017 02;46(2):261-272

Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012 Paris, France. Electronic address:

Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.
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http://dx.doi.org/10.1016/j.immuni.2017.01.006DOI Listing
February 2017

Protection of Glial Müller Cells by Dexamethasone in a Mouse Model of Surgically Induced Blood-Retinal Barrier Breakdown.

Invest Ophthalmol Vis Sci 2017 02;58(2):876-886

Sorbonne Universités, Pierre et Marie Curie University, University Paris 06, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique Institut de la Vision, Paris, France 6Ophthalmology Department, Avicenne Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), University Paris 13, DHU Vision and Handicaps, Bobigny, France.

Purpose: Breakdown of the inner blood-retinal barrier (iBRB) occurs in many retinal disorders and may cause retinal edema often responsible for vision loss. Dexamethasone is used in clinical practice to restore iBRB. The aim of this study was to characterize the impact of a surgically induced iBRB breakdown on retinal homeostatic changes due to dystrophin Dp71, aquaporin-4 (AQP4), and Kir4.1 alterations in Müller glial cells (MGC) in a mouse model. The protective effect of dexamethasone was assessed in this model. Moreover, retinal explants were used to control MGC exposure to a hypoosmotic solution containing barium.

Methods: Partial lens surgery was performed in C57BL6/J mice. Dystrophin Dp71, AQP4, and Kir4.1 expression was analyzed by quantitative RT-PCR, Western blot, and immunohistochemistry. Twenty-four hours after surgery, mice received a single intravitreal injection of dexamethasone or of vehicle.

Results: After partial lens surgery, iBRB permeability increased while Dp71 and AQP4 were downregulated and Kir4.1 was delocalized. These effects were partially prevented by dexamethasone injection. In the retinal explant model, MGC were swollen and Dp71, AQP4, and Kir4.1 were downregulated after exposure to a hypoosmotic solution containing barium, but not in the presence of dexamethasone. Heat shock factor protein 1 (HSF1) was overexpressed in dexamethasone-treated retinas.

Conclusions: Partial lens surgery induces iBRB breakdown and molecular changes in MGC, including a downregulation of Dp71 and AQP4 and the delocalization of Kir4.1. Dexamethasone seems to protect retina from these molecular changes by upregulating HSF1.
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http://dx.doi.org/10.1167/iovs.16-20617DOI Listing
February 2017

Cone Genesis Tracing by the Chrnb4-EGFP Mouse Line: Evidences of Cellular Material Fusion after Cone Precursor Transplantation.

Mol Ther 2017 03 28;25(3):634-653. Epub 2017 Jan 28.

Unit of Retinal Degeneration and Regeneration, Department of Ophthalmology, University of Lausanne, Hôpital ophtalmique Jules-Gonin, Fondation asile des aveugles, 1004 Lausanne, Switzerland. Electronic address:

The cone function is essential to mediate high visual acuity, color vision, and daylight vision. Inherited cone dystrophies and age-related macular degeneration affect a substantial percentage of the world population. To identify and isolate the most competent cells for transplantation and integration into the retina, cone tracing during development would be an important added value. To that aim, the Chrnb4-EGFP mouse line was characterized throughout retinogenesis. It revealed a sub-population of early retinal progenitors expressing the reporter gene that is progressively restricted to mature cones during retina development. The presence of the native CHRNB4 protein was confirmed in EGFP-positive cells, and it presents a similar pattern in the human retina. Sub-retinal transplantations of distinct subpopulations of Chrnb4-EGFP-expressing cells revealed the embryonic day 15.5 high-EGFP population the most efficient cells to interact with host retinas to provoke the appearance of EGFP-positive cones in the photoreceptor layer. Importantly, transplantations into the DsRed retinas revealed material exchanges between donor and host retinas, as >80% of transplanted EGFP-positive cones also were DsRed positive. Whether this cell material fusion is of significant therapeutic advantage requires further thorough investigations. The Chrnb4-EGFP mouse line definitely opens new research perspectives in cone genesis and retina repair.
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http://dx.doi.org/10.1016/j.ymthe.2016.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363218PMC
March 2017

Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome.

Neurobiol Dis 2017 Apr 3;100:52-61. Epub 2017 Jan 3.

INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France. Electronic address:

The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling.

Summary Statement: This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition.
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http://dx.doi.org/10.1016/j.nbd.2016.12.014DOI Listing
April 2017

Lebecetin, a C-type lectin, inhibits choroidal and retinal neovascularization.

FASEB J 2017 03 14;31(3):1107-1119. Epub 2016 Dec 14.

Sorbonne Universités, Université Pierre et Marie Curie, INSERM, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France;

Angiogenesis is a cause of visual impairment and blindness in the wet form of age-related macular degeneration and in ischemic retinopathies. Current therapies include use of anti-VEGF agents to reduce choroidal neovascularization (CNV) and edema. These treatments are effective in most cases, but spontaneous or acquired resistance to anti-VEGF and possible adverse effects of long-term VEGF inhibition in the retina and choroid highlight a need for additional alternative therapies. Integrins αvβ3 and αvβ5, which regulate endothelial cell proliferation and stabilization, have been implicated in ocular angiogenesis. Lebecetin (LCT) is a 30-kDa heterodimeric C-type lectin that is isolated from venom and interacts with α5β1- and αv-containing integrins. We previously showed that LCT inhibits human brain microvascular endothelial cell adhesion, migration, proliferation, and tubulogenesis. To evaluate the inhibitory effect of LCT on ocular angiogenesis, we cultured aortic and choroidal explants in the presence of LCT and analyzed the effect of LCT on CNV in the mouse CNV model and on retinal neovascularization in the oxygen-induced retinopathy model. Our data demonstrate that a single injection of LCT efficiently reduced CNV and retinal neovascularization in these models.-Montassar, F., Darche, M., Blaizot, A., Augustin, S., Conart, J.-B., Millet, A., Elayeb, M., Sahel, J.-A., Réaux-Le Goazigo, A., Sennlaub, F., Marrakchi, N., Messadi, E., Guillonneau, X. Lebecetin, a C-type lectin, inhibits choroidal and retinal neovascularization.
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http://dx.doi.org/10.1096/fj.201600351RDOI Listing
March 2017