Publications by authors named "Hugo Charles-Messance"

13 Publications

  • Page 1 of 1

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

Regulating metabolic inflammation by nutritional modulation.

J Allergy Clin Immunol 2020 10 22;146(4):706-720. Epub 2020 Aug 22.

Nutrigenomics Research Group, School of Public Health Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland; University College Dublin Institute of Food and Health/Diabetes Complications Research Centre, University College Dublin Conway Institute, University College Dublin, Dublin, Ireland; Institute for Global Food Security, Queens University Belfast, Belfast, United Kingdom. Electronic address:

Metabolic inflammation (metaflammation) is characteristic of obesity-related metabolic disorders, associated with increased risk of development of type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), or cardiovascular disease. Metaflammation refers to a chronic, low-grade systemic inflammation as opposed to the classical transient and acute inflammatory responses of the innate immune system. Metaflammation is driven by a range of adverse dietary factors, including saturated fatty acids and some sugars, suggesting that certain dietary triggers may be particularly relevant beyond simple excessive dietary intake presenting as obesity. Importantly, obese patients with diabetes have a higher risk of infection and display gut microbiota profiles characteristic of dysfunctional immunity. Targeting metaflammation has also emerged as a strategy to attenuate metabolic disease. In this review we explore how different nutrition interventions may reconfigure disrupted metabolic inflammation in type 2 diabetes and nonalcoholic fatty liver disease by reestablishing a conventional proinflammatory program in innate immune cells and/or correcting dysbiosis to dampen systemic inflammation. We begin by reviewing concepts of metabolic inflammation relating to IL-1β inflammation and how it is induced by dietary and/or metabolic stressors. We then explore whether and how dietary interventions may attenuate processes pertaining to metaflammation, either directly or indirectly via the microbiome. Hence, we hope to bring new perspectives to alleviate the metaflammation typifying metabolic disease.
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http://dx.doi.org/10.1016/j.jaci.2020.08.013DOI Listing
October 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

Train to Lose: Innate Immune Memory in Metaflammation.

Mol Nutr Food Res 2021 01 25;65(1):e1900480. Epub 2020 Jun 25.

Macrophage Homeostasis Research Group, School of Biochemistry and Immunology, Trinity College, Dublin, D02 R590, Ireland.

Westernized diets and lifestyle are linked to the development of metabolic syndrome, characterized by obesity, type 2 diabetes, and increased cardiovascular disease risk. Systemic low-grade inflammation is a common feature of chronic metabolic disorders and is believed to promote disease progression. Therefore, modulating inflammation is a commonly explored strategy to prevent obesity-associated co-morbidities. In this review, how current knowledge on the recently described concept of innate immune memory could underline metaflammation in the context of metabolic syndrome is explored. It is hoped that these insights provide a new perspective to address the question of innate immune activation during disease progression.
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http://dx.doi.org/10.1002/mnfr.201900480DOI Listing
January 2021

Mycobacterium tuberculosis Limits Host Glycolysis and IL-1β by Restriction of PFK-M via MicroRNA-21.

Cell Rep 2020 01;30(1):124-136.e4

School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland; Conway Institute, University College Dublin, Dublin, Ireland. Electronic address:

Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1β (IL-1β). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function.
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http://dx.doi.org/10.1016/j.celrep.2019.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764301PMC
January 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

Expression and localization of dystrophins and β-dystroglycan in the hypothalamic supraoptic nuclei of rat from birth to adulthood.

Acta Histochem 2019 Feb 28;121(2):218-226. Epub 2018 Dec 28.

Equipe de Neurochimie, LBPO, Faculté des Sciences Biologiques, USTHB, Alger, Algeria.

Dystrophins (Dps) are the sub-membranous proteins that work via the dystrophin-associated proteins complex, which comprises β-dystroglycan (β-DG), a cell surface receptor for extracellular matrix. Recently, we have revealed β-DG decrease and central function impairment of supraoptic nucleus (SON) in Dp71 deficient adult mice, opening the question on the profiles of Dps and β-DG during SON development. At birth and the age of 10, 20 and 60 days, we examined the expression by RT-PCR and Western-blotting, and the distribution by immunohistochemistry of Dps and β-DG. Also, we analyzed, by immunohistochemistry and Western-blotting, the neuropeptide, arginine vasopressin (AVP), in the SON at the different ages. At birth, Dp71 and to a lesser extends, Dp140 and Dp427, and also β-DG are revealed in the SON. They are localized in the magnocellular neurons (MCNs), astrocytes and vessels. From birth to adulthood, the AVP raise in the SON coincides with the progressive increase of Dp71 level while the level of Dp140 and Dp427 increased only at D20, D10 post-natal development, respectively, and β-DG expression did not change. Moreover, the location of Dps or/and β-DG in the cell compartments was modified during development: at D10, Dps appeared in the astrocytes end-feet surrounding MCNs, and at D20, Dps and β-DG codistributed in the astrocytes end-feet, surrounding MCNs and vessels. Such a distribution marks the first steps of post-natal SON development and may be considered essential in the establishment of structural plasticity mechanisms in SON, where astrocyte end-feet, vessels, magnocellular neurons, are physiologically associated. The disappearance of β-DG in the MCNs nucleus marks the adulthood SON and suggests that the complex of Dps associating β-DG is required for the nucleoskeleton function in the post-natal development.
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http://dx.doi.org/10.1016/j.acthis.2018.12.001DOI Listing
February 2019

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

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

Subretinal mononuclear phagocytes induce cone segment loss via IL-1β.

Elife 2016 07 20;5. Epub 2016 Jul 20.

Sorbonne Universités, UPMC University Paris 06, INSERM, CNRS, Paris, France.

Photo-transduction in cone segments (CS) is crucial for high acuity daytime vision. For ill-defined reasons, CS degenerate in retinitis pigmentosa (RP) and in the transitional zone (TZ) of atrophic zones (AZ), which characterize geographic atrophy (GA). Our experiments confirm the loss of cone segments (CS) in the TZ of patients with GA and show their association with subretinal CD14(+)mononuclear phagocyte (MP) infiltration that is also reported in RP. Using human and mouse MPs in vitro and inflammation-prone Cx3cr1(GFP/GFP) mice in vivo, we demonstrate that MP-derived IL-1β leads to severe CS degeneration. Our results strongly suggest that subretinal MP accumulation participates in the observed pathological photoreceptor changes in these diseases. Inhibiting subretinal MP accumulation or Il-1β might protect the CS and help preserve high acuity daytime vision in conditions characterized by subretinal inflammation, such as AMD and RP.
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http://dx.doi.org/10.7554/eLife.16490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969036PMC
July 2016

AAV-mediated gene therapy in Dystrophin-Dp71 deficient mouse leads to blood-retinal barrier restoration and oedema reabsorption.

Hum Mol Genet 2016 07 10;25(14):3070-3079. Epub 2016 Jun 10.

Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 75012 Paris, France.

Dystrophin-Dp71 being a key membrane cytoskeletal protein, expressed mainly in Müller cells that provide a mechanical link at the Müller cell membrane by direct binding to actin and a transmembrane protein complex. Its absence has been related to blood-retinal barrier (BRB) permeability through delocalization and down-regulation of the AQP4 and Kir4.1 channels (1). We have previously shown that the adeno-associated virus (AAV) variant, ShH10, transduces Müller cells in the Dp71-null mouse retina efficiently and specifically (2,3). Here, we use ShH10 to restore Dp71 expression in Müller cells of Dp71 deficient mouse to study molecular and functional effects of this restoration in an adult mouse displaying retinal permeability. We show that strong and specific expression of exogenous Dp71 in Müller cells leads to correct localization of Dp71 protein restoring all protein interactions in order to re-establish a proper functional BRB and retina homeostasis thus preventing retina from oedema. This study is the basis for the development of new therapeutic strategies in dealing with diseases with BRB breakdown and macular oedema such as diabetic retinopathy (DR).
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http://dx.doi.org/10.1093/hmg/ddw159DOI Listing
July 2016

Dystrophin Dp71 gene deletion induces retinal vascular inflammation and capillary degeneration.

Hum Mol Genet 2015 Jul 21;24(14):3939-47. Epub 2015 Apr 21.

Institut de la Vision/INSERM/UPMC, Univ Paris 06/CNRS/CHNO des Quinze-Vingts, Paris, France, Ophthalmology Department, Hôpital Lariboisière (AP-HP) 2, Université Paris 7, Sorbonne Paris Cité, rue Ambroise Paré, 75010 Paris, France

We have previously shown that the deletion of the dystrophin Dp71 gene induces a highly permeable blood-retinal barrier (BRB). Given that BRB breakdown is involved in retinal inflammation and the pathophysiology of many blinding eye diseases, here we investigated whether the absence of Dp71 brings out retinal vascular inflammation and vessel loss by using specific Dp71-null mice. The expression of vascular endothelial growth factor (VEGF), quantified by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay methods, was higher in the retina of Dp71-null mice than in wild-type mice. In contrast, no differences were observed in VEGFR-2 and tumor necrosis factor-α expression. Moreover, mRNA expression of water channel, aquaporin 4 (AQP4) was increased after Dp71 deletion. The Dp71 deletion was also associated with the overexpression of intercellular adhesion molecule 1, which is expressed on endothelial cells surface to recruit leukocytes. Consistent with these findings, the total number of adherent leukocytes per retina, assessed after perfusion with fluorescein isothiocyanate-conjugated concanavalin A, was increased in the absence of Dp71. Finally, a significant increase in capillary degeneration quantified after retinal trypsin digestion was observed in mice lacking Dp71. These data illustrate for the first time that the deletion of Dp71 was associated with retinal vascular inflammation, vascular lesions with increased leukocyte adhesion and capillary degeneration. Thus, dystrophin Dp71 could play a critical role in retinal vascular inflammation disease, and therefore represent a potential therapeutic target.
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http://dx.doi.org/10.1093/hmg/ddv132DOI Listing
July 2015
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