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  1. AU="Blot, Guillaume"
  2. AU="Sanchez, Gabriela"
  3. AU=Mitton Julian A
  4. AU="Han, Hyunho"
  5. AU="Shama, Noura M Abo"
  6. AU=Uehara Akira
  7. AU=Fransen Justin H AU=Fransen Justin H
  8. AU="Memon, Roha Saeed"
  9. AU="Lipworth, Samuel"
  10. AU="Killian, Michael O"
  11. AU=Smaldino Paul E.
  12. AU=Bi Hai
  13. AU="Pintore, Giorgio"
  14. AU="Signorini C."
  15. AU="Mameli, Maria Sabrina"
  16. AU="Yong-ming GAO"
  17. AU="Paquette, Kimberly"
  18. AU="Sharawat, Indar Kumar"
  19. AU="Alexandre Alanio"
  20. AU="Caron, Jeffrey G"
  21. AU="Lubisi, Baratang A"
  22. AU="Edelman, Robert R."
  23. AU="van der Werf, Steffie"
  24. AU="Sam, Andrew"

Suchergebnis

Treffer 1 - 10 von insgesamt 19

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  1. Artikel ; Online: Why

    Blot, Guillaume / Shokri, Leila / Buttery, Shawnna

    STAR protocols

    2022  Band 3, Heft 2, Seite(n) 101395

    Abstract: When researchers submit a protocol for peer review and publication, they receive feedback from reviewers to help improve the usability of the protocol. These authors can be the perfect peer reviewers helping propel research forward. They can use their ... ...

    Abstract When researchers submit a protocol for peer review and publication, they receive feedback from reviewers to help improve the usability of the protocol. These authors can be the perfect peer reviewers helping propel research forward. They can use their technical expertise and sharpened writing skills to help improve the main aspects of published protocols, namely their clarity and reproducibility. This backstory chronicles the journey of Dr. Guillaume Blot, from a junior researcher and author to a protocol reviewer. For complete details, please refer to Blot et al. (2021).
    Mesh-Begriff(e) Humans ; Peer Group ; Peer Review ; Professional Competence ; Reproducibility of Results ; Research Personnel
    Sprache Englisch
    Erscheinungsdatum 2022-05-11
    Erscheinungsland United States
    Dokumenttyp News
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2022.101395
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Modifications to the classical rat aortic ring model to allow vascular degeneration studies.

    Blot, Guillaume / Sartoris, Thérèse-Marie / Sennlaub, Florian / Guillonneau, Xavier

    STAR protocols

    2021  Band 2, Heft 1, Seite(n) 100281

    Abstract: 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 ... ...

    Abstract 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.
    Mesh-Begriff(e) Animals ; Aorta/metabolism ; Capillaries/metabolism ; Neovascularization, Physiologic ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley
    Sprache Englisch
    Erscheinungsdatum 2021-01-21
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2020.100281
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: HIF1α-dependent hypoxia response in myeloid cells requires IRE1α.

    Mawambo, Gaëlle / Oubaha, Malika / Ichiyama, Yusuke / Blot, Guillaume / Crespo-Garcia, Sergio / Dejda, Agnieszka / Binet, François / Diaz-Marin, Roberto / Sawchyn, Christina / Sergeev, Mikhail / Juneau, Rachel / Kaufman, Randal J / Affar, El Bachir / Mallette, Frédérick A / Wilson, Ariel M / Sapieha, Przemyslaw

    Journal of neuroinflammation

    2023  Band 20, Heft 1, Seite(n) 145

    Abstract: Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to ... ...

    Abstract Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to function under low oxygen tension and metabolic stress. While Hypoxia-Inducible Factor (HIF)-1α has been shown to be essential for the inflammatory response of myeloid cells by regulating the metabolic switch to glycolysis, less is known about how HIF1α is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1α (IRE1α/XBP1) axis in order to initiate HIF1α-dependent production of cytokines such as IL1β, IL6 and VEGF-A. Knockout of either HIF1α or IRE1α in myeloid cells ameliorates vascular phenotypes in a model of retinal pathological angiogenesis driven by sterile inflammation. Thus, pathways associated with ER stress, in partnership with HIF1α, may co-regulate immune adaptation to low oxygen.
    Mesh-Begriff(e) Humans ; Protein Serine-Threonine Kinases/genetics ; Endoribonucleases ; Hypoxia ; Oxygen/metabolism ; Myeloid Cells/metabolism ; Inflammation/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit
    Chemische Substanzen Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-) ; Oxygen (S88TT14065) ; Hypoxia-Inducible Factor 1, alpha Subunit
    Sprache Englisch
    Erscheinungsdatum 2023-06-21
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2156455-3
    ISSN 1742-2094 ; 1742-2094
    ISSN (online) 1742-2094
    ISSN 1742-2094
    DOI 10.1186/s12974-023-02793-y
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  4. Artikel ; Online: Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results.

    Crespo-Garcia, Sergio / Fournier, Frédérik / Diaz-Marin, Roberto / Klier, Sharon / Ragusa, Derek / Masaki, Lauren / Cagnone, Gael / Blot, Guillaume / Hafiane, Ikhlas / Dejda, Agnieszka / Rizk, Rana / Juneau, Rachel / Buscarlet, Manuel / Chorfi, Sarah / Patel, Priyanka / Beltran, Pedro J / Joyal, Jean-Sebastien / Rezende, Flavio A / Hata, Masayuki /
    Nguyen, Alex / Sullivan, Lynne / Damiano, Jason / Wilson, Ariel M / Mallette, Frédérick A / David, Nathaniel E / Ghosh, Anirvan / Tsuruda, Pamela R / Dananberg, Jamie / Sapieha, Przemyslaw

    Nature medicine

    2024  Band 30, Heft 2, Seite(n) 443–454

    Abstract: Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal ... ...

    Abstract Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .
    Mesh-Begriff(e) Animals ; Mice ; Humans ; Macular Edema/drug therapy ; Macular Edema/etiology ; Diabetic Retinopathy/drug therapy ; Angiogenesis Inhibitors/therapeutic use ; Endothelial Cells ; Senotherapeutics ; Cellular Senescence ; Diabetes Mellitus
    Chemische Substanzen Angiogenesis Inhibitors ; Senotherapeutics
    Sprache Englisch
    Erscheinungsdatum 2024-02-06
    Erscheinungsland United States
    Dokumenttyp Clinical Trial, Phase I ; Journal Article
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-024-02802-4
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Perilipin 2-positive mononuclear phagocytes accumulate in the diabetic retina and promote PPARγ-dependent vasodegeneration.

    Blot, Guillaume / Karadayi, Rémi / Przegralek, Lauriane / Sartoris, Thérèse-Marie / Charles-Messance, Hugo / Augustin, Sébastien / Negrier, Pierre / Blond, Frédéric / Muñiz-Ruvalcaba, Frida Paulina / Rivera-de la Parra, David / Vignaud, Lucile / Couturier, Aude / Sahel, José-Alain / Acar, Niyazi / Jimenez-Corona, Aida / Delarasse, Cécile / Garfias, Yonathan / Sennlaub, Florian / Guillonneau, Xavier

    The Journal of clinical investigation

    2023  Band 133, Heft 19

    Abstract: Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and dyslipidemia, leads to nonproliferative diabetic retinopathy (NPDR). NPDR is associated with blood-retina barrier disruption, plasma exudates, microvascular degeneration, elevated ... ...

    Abstract Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and dyslipidemia, leads to nonproliferative diabetic retinopathy (NPDR). NPDR is associated with blood-retina barrier disruption, plasma exudates, microvascular degeneration, elevated inflammatory cytokine levels, and monocyte (Mo) infiltration. Whether and how the diabetes-associated changes in plasma lipid and carbohydrate levels modify Mo differentiation remains unknown. Here, we show that mononuclear phagocytes (MPs) in areas of vascular leakage in DR donor retinas expressed perilipin 2 (PLIN2), a marker of intracellular lipid load. Strong upregulation of PLIN2 was also observed when healthy donor Mos were treated with plasma from patients with T2DM or with palmitate concentrations typical of those found in T2DM plasma, but not under high-glucose conditions. PLIN2 expression correlated with the expression of other key genes involved in lipid metabolism (ACADVL, PDK4) and the DR biomarkers ANGPTL4 and CXCL8. Mechanistically, we show that lipid-exposed MPs induced capillary degeneration in ex vivo explants that was inhibited by pharmaceutical inhibition of PPARγ signaling. Our study reveals a mechanism linking dyslipidemia-induced MP polarization to the increased inflammatory cytokine levels and microvascular degeneration that characterize NPDR. This study provides comprehensive insights into the glycemia-independent activation of Mos in T2DM and identifies MP PPARγ as a target for inhibition of lipid-activated MPs in DR.
    Mesh-Begriff(e) Humans ; Cytokines/metabolism ; Diabetes Mellitus, Type 2/genetics ; Diabetic Retinopathy/genetics ; Dyslipidemias/metabolism ; Lipids ; Macrophages/metabolism ; Perilipin-2/genetics ; Perilipin-2/metabolism ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Retina/metabolism
    Chemische Substanzen Cytokines ; Lipids ; Perilipin-2 ; PPAR gamma ; PLIN2 protein, human
    Sprache Englisch
    Erscheinungsdatum 2023-10-02
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI161348
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  6. Artikel ; Online: Past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation.

    Hata, Masayuki / Andriessen, Elisabeth M M A / Hata, Maki / Diaz-Marin, Roberto / Fournier, Frédérik / Crespo-Garcia, Sergio / Blot, Guillaume / Juneau, Rachel / Pilon, Frédérique / Dejda, Agnieszka / Guber, Vera / Heckel, Emilie / Daneault, Caroline / Calderon, Virginie / Des Rosiers, Christine / Melichar, Heather J / Langmann, Thomas / Joyal, Jean-Sebastien / Wilson, Ariel M /
    Sapieha, Przemyslaw

    Science (New York, N.Y.)

    2023  Band 379, Heft 6627, Seite(n) 45–62

    Abstract: Age-related macular degeneration is a prevalent neuroinflammatory condition and a major cause of blindness driven by genetic and environmental factors such as obesity. In diseases of aging, modifiable factors can be compounded over the life span. We ... ...

    Abstract Age-related macular degeneration is a prevalent neuroinflammatory condition and a major cause of blindness driven by genetic and environmental factors such as obesity. In diseases of aging, modifiable factors can be compounded over the life span. We report that diet-induced obesity earlier in life triggers persistent reprogramming of the innate immune system, lasting long after normalization of metabolic abnormalities. Stearic acid, acting through Toll-like receptor 4 (TLR4), is sufficient to remodel chromatin landscapes and selectively enhance accessibility at binding sites for activator protein-1 (AP-1). Myeloid cells show less oxidative phosphorylation and shift to glycolysis, ultimately leading to proinflammatory cytokine transcription, aggravation of pathological retinal angiogenesis, and neuronal degeneration associated with loss of visual function. Thus, a past history of obesity reprograms mononuclear phagocytes and predisposes to neuroinflammation.
    Mesh-Begriff(e) Animals ; Mice ; Cytokines/genetics ; Immunity, Innate/genetics ; Neuroinflammatory Diseases/genetics ; Neuroinflammatory Diseases/immunology ; Obesity/genetics ; Phagocytes/immunology ; Transcription, Genetic ; Macular Degeneration/genetics ; Macular Degeneration/immunology ; Cellular Reprogramming/genetics ; Epigenetic Memory ; Toll-Like Receptor 4/genetics
    Chemische Substanzen Cytokines ; Tlr4 protein, mouse ; Toll-Like Receptor 4
    Sprache Englisch
    Erscheinungsdatum 2023-01-05
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.abj8894
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  7. Artikel ; Online: Reproducing diabetic retinopathy features using newly developed human induced-pluripotent stem cell-derived retinal Müller glial cells.

    Couturier, Aude / Blot, Guillaume / Vignaud, Lucile / Nanteau, Céline / Slembrouck-Brec, Amélie / Fradot, Valérie / Acar, Niyazi / Sahel, José-Alain / Tadayoni, Ramin / Thuret, Gilles / Sennlaub, Florian / Roger, Jerome E / Goureau, Olivier / Guillonneau, Xavier / Reichman, Sacha

    Glia

    2021  Band 69, Heft 7, Seite(n) 1679–1693

    Abstract: 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. ... ...

    Abstract 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.
    Mesh-Begriff(e) Diabetes Mellitus/metabolism ; Diabetic Retinopathy ; Ependymoglial Cells/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Neuroglia/metabolism ; Retina
    Sprache Englisch
    Erscheinungsdatum 2021-03-08
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639414-0
    ISSN 1098-1136 ; 0894-1491
    ISSN (online) 1098-1136
    ISSN 0894-1491
    DOI 10.1002/glia.23983
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  8. Artikel ; Online: Insulin inhibits inflammation-induced cone death in retinal detachment.

    Conart, Jean-Baptiste / Blot, Guillaume / Augustin, Sébastien / Millet-Puel, Géraldine / Roubeix, Christophe / Beguier, Fanny / Charles-Messance, Hugo / Touhami, Sara / Sahel, José-Alain / Berrod, Jean-Paul / Léveillard, Thierry / Guillonneau, Xavier / Delarasse, Cécile / Sennlaub, Florian

    Journal of neuroinflammation

    2020  Band 17, Heft 1, Seite(n) 358

    Abstract: 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 ... ...

    Abstract 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.
    Mesh-Begriff(e) Adult ; Animals ; Cell Death/physiology ; Eye Proteins/metabolism ; Female ; Glucose/metabolism ; Humans ; Hypoglycemic Agents/pharmacology ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Insulin/pharmacology ; Male ; Metformin/pharmacology ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Retinal Cone Photoreceptor Cells/drug effects ; Retinal Cone Photoreceptor Cells/metabolism ; Retinal Cone Photoreceptor Cells/pathology ; Retinal Detachment/immunology ; Retinal Detachment/metabolism ; Retinal Detachment/pathology ; Rosiglitazone/pharmacology ; Thioredoxins/metabolism
    Chemische Substanzen Eye Proteins ; Hypoglycemic Agents ; Insulin ; RdCVF protein, mouse ; Rosiglitazone (05V02F2KDG) ; Thioredoxins (52500-60-4) ; Metformin (9100L32L2N) ; Glucose (IY9XDZ35W2)
    Sprache Englisch
    Erscheinungsdatum 2020-11-26
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2156455-3
    ISSN 1742-2094 ; 1742-2094
    ISSN (online) 1742-2094
    ISSN 1742-2094
    DOI 10.1186/s12974-020-02039-1
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  9. Artikel ; Online: IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis.

    Charles-Messance, Hugo / Blot, Guillaume / Couturier, Aude / Vignaud, Lucile / Touhami, Sara / Beguier, Fanny / Siqueiros, Lourdes / Forster, Valérie / Barmo, Nour / Augustin, Sébastien / Picaud, Serge / Sahel, José-Alain / Rendon, Alvaro / Grosche, Antje / Tadayoni, Ramin / Sennlaub, Florian / Guillonneau, Xavier

    Journal of neuroinflammation

    2020  Band 17, Heft 1, Seite(n) 1

    Abstract: 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 ... ...

    Abstract 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.
    Mesh-Begriff(e) Animals ; Coculture Techniques ; Glutamic Acid/metabolism ; Homeostasis/drug effects ; Homeostasis/physiology ; Humans ; Interleukin-1beta/toxicity ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Monocytes/drug effects ; Monocytes/metabolism ; Retinal Degeneration/chemically induced ; Retinal Degeneration/metabolism ; Retinal Rod Photoreceptor Cells/drug effects ; Retinal Rod Photoreceptor Cells/metabolism
    Chemische Substanzen IL1B protein, mouse ; Interleukin-1beta ; Glutamic Acid (3KX376GY7L)
    Sprache Englisch
    Erscheinungsdatum 2020-01-03
    Erscheinungsland England
    Dokumenttyp Journal Article
    ISSN 1742-2094
    ISSN (online) 1742-2094
    DOI 10.1186/s12974-019-1655-5
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: In vitro, in cellulo and structural characterizations of the interaction between the integrase of Porcine Endogenous Retrovirus A/C and proteins of the BET family.

    Gallay, Kathy / Blot, Guillaume / Chahpazoff, Margaux / Yajjou-Hamalian, Halima / Confort, Marie-Pierre / De Boisséson, Claire / Leroux, Aurélie / Luengo, Catherine / Fiorini, Francesca / Lavigne, Marc / Chebloune, Yahia / Gouet, Patrice / Moreau, Karen / Blanchard, Yannick / Ronfort, Corinne

    Virology

    2019  Band 532, Seite(n) 69–81

    Abstract: Retroviral integrase (IN) proteins catalyze the permanent integration of the viral genome into host DNA. They can productively recruit cellular proteins, and the human Bromodomain and Extra-Terminal domain (hBET) proteins have been shown to be co-factors ...

    Abstract Retroviral integrase (IN) proteins catalyze the permanent integration of the viral genome into host DNA. They can productively recruit cellular proteins, and the human Bromodomain and Extra-Terminal domain (hBET) proteins have been shown to be co-factors for integration of gamma-retroviruses such as Murine Leukemia Virus (MLV) into human cells. By using two-hybrid, co-immunoprecipitation and in vitro interaction assays, we showed that IN of the gamma- Porcine Endogenous Retrovirus-A/C (PERV IN) interacts through its C-terminal domain (CTD) with hBET proteins. We observed that PERV IN interacts with the BRD2, BRD3 and BRD4 proteins in vitro and that the BRD2 protein specifically binds and co-localizes with PERV IN protein in the nucleus of cells. We further mapped the interaction sites to the conserved Extra-Terminal (ET) domain of the hBET proteins and to several amino acids of the of the C-terminal tail of the PERV IN CTD. Finally, we determined the first experimental structure of an IN CTD - BET ET complex from small-angle X-ray scattering data (SAXS). We showed that the two factors assemble as two distinct modules linked by a short loop which confers partial flexibility. The SAXS-restrained model is structurally compatible with the binding of the PERV intasome to BRD2. Altogether, these data confirm the important role of host BET proteins in the gamma-retroviruses' targeting site and efficiency of integration.
    Mesh-Begriff(e) Amino Acid Sequence ; Animals ; Binding Sites ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Nucleus/metabolism ; Cell Nucleus/virology ; Crystallography, X-Ray ; Endogenous Retroviruses/genetics ; Endogenous Retroviruses/metabolism ; Gene Expression ; Gene Expression Regulation ; HEK293 Cells ; Host-Pathogen Interactions/genetics ; Humans ; Integrases/chemistry ; Integrases/genetics ; Integrases/metabolism ; Models, Molecular ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sequence Alignment ; Sequence Homology, Amino Acid ; Swine ; Transcription Factors/chemistry ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Virus Integration
    Chemische Substanzen BRD2 protein, human ; BRD3 protein, human ; BRD4 protein, human ; Cell Cycle Proteins ; Recombinant Proteins ; Transcription Factors ; Integrases (EC 2.7.7.-)
    Sprache Englisch
    Erscheinungsdatum 2019-04-16
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 200425-2
    ISSN 1096-0341 ; 0042-6822
    ISSN (online) 1096-0341
    ISSN 0042-6822
    DOI 10.1016/j.virol.2019.04.002
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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