CXCR3 Antagonism of SDF-1(5-67) Restores Trabecular Function and Prevents Retinal Neurodegeneration in a Rat Model of Ocular Hypertension
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{"title"=>"CXCR3 antagonism of SDF-1(5-67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension", "type"=>"journal", "authors"=>[{"first_name"=>"Alexandre", "last_name"=>"Denoyer", "scopus_author_id"=>"15834282100"}, {"first_name"=>"David", "last_name"=>"Godefroy", "scopus_author_id"=>"7004465941"}, {"first_name"=>"Isabelle", "last_name"=>"Célérier", "scopus_author_id"=>"39461076000"}, {"first_name"=>"Julie", "last_name"=>"Frugier", "scopus_author_id"=>"55241519300"}, {"first_name"=>"Julie", "last_name"=>"Degardin", "scopus_author_id"=>"36142801900"}, {"first_name"=>"Jeffrey K.", "last_name"=>"Harrison", "scopus_author_id"=>"7402742158"}, {"first_name"=>"Francoise", "last_name"=>"Brignole-Baudouin", "scopus_author_id"=>"7801411514"}, {"first_name"=>"Serge", "last_name"=>"Picaud", "scopus_author_id"=>"7006229322"}, {"first_name"=>"Francoise", "last_name"=>"Baleux", "scopus_author_id"=>"6701913982"}, {"first_name"=>"José A.", "last_name"=>"Sahel", "scopus_author_id"=>"7101991490"}, {"first_name"=>"William", "last_name"=>"Rostène", "scopus_author_id"=>"56284440900"}, {"first_name"=>"Christophe", "last_name"=>"Baudouin", "scopus_author_id"=>"7102848002"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22675496", "sgr"=>"84861889862", "doi"=>"10.1371/journal.pone.0037873", "scopus"=>"2-s2.0-84861889862", "pui"=>"364955402", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203"}, "id"=>"dfa3e24e-f3b9-38b6-8c99-dceb8ff12097", "abstract"=>"Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.", "link"=>"http://www.mendeley.com/research/cxcr3-antagonism-sdf1567-restores-trabecular-function-prevents-retinal-neurodegeneration-rat-model-o", "reader_count"=>16, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Student > Doctoral Student"=>4, "Researcher"=>1, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>3, "Student > Master"=>3, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Student > Doctoral Student"=>4, "Researcher"=>1, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>3, "Student > Master"=>3, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>5, "Psychology"=>1, "Unspecified"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/628571"], "description"=>"<p><i>(A)</i> Aqueous humor outflow impairment in hypertensive eyes is counteracted by treatment with CXCR3 antagonist as measured <i>in vivo</i> by fluorophotometry (n = 10 each). <i>(B,C,D)</i> Trabecular filtrating function is restored by treatment with CXCR3 antagonist as assessed by trabecular trapping of fluorescent microspheres (red), and quantitatively measured as percent of effective filtration length (PEFL), which is more important in treated eyes <i>(B)</i> than in untreated hypertensive eyes <i>(C)</i> (n = 10 each). <i>(E,F,G)</i> Density of apoptotic trabecular cells is lower in eyes treated with the CXCR3 antagonist <i>(E)</i> than in untreated hypertensive eyes <i>(F),</i> as assessed by TUNEL (green) and DAPI (blue) nuclear staining (n = 10 each). ** <i>P</i><0.01. (scale bar, 50 µm). Data in bar graphs are presented as means ± SEM.</p>", "links"=>[], "tags"=>["cxcr3", "antagonist", "restores", "trabecular", "filtrating", "protects", "cells", "apoptosis", "ocular"], "article_id"=>299040, "categories"=>["Physiology", "Neuroscience", "Cell Biology", "Medicine"], "users"=>["Alexandre Denoyer", "David Godefroy", "Isabelle Célérier", "Julie Frugier", "Julie Degardin", "Jeffrey K. Harrison", "Françoise Brignole-Baudouin", "Serge Picaud", "Françoise Baleux", "José A. Sahel", "William Rostène", "Christophe Baudouin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037873.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ophthalmic_administration_of_CXCR3_antagonist_restores_trabecular_filtrating_function_and_protects_trabecular_cells_from_apoptosis_in_a_rat_model_of_ocular_hypertension_/299040", "title"=>"Ophthalmic administration of CXCR3 antagonist restores trabecular filtrating function and protects trabecular cells from apoptosis in a rat model of ocular hypertension.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-04 02:30:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/325715", "https://ndownloader.figshare.com/files/325723", "https://ndownloader.figshare.com/files/325774"], "description"=>"<div><p>Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects <em>in vitro</em> trabecular cells from apoptotic death <em>via</em> CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.</p> </div>", "links"=>[], "tags"=>["cxcr3", "antagonism", "restores", "trabecular", "prevents", "retinal", "neurodegeneration", "ocular", "hypertension"], "article_id"=>124282, "categories"=>["Physiology", "Neuroscience", "Cell Biology", "Medicine"], "users"=>["Alexandre Denoyer", "David Godefroy", "Isabelle Célérier", "Julie Frugier", "Julie Degardin", "Jeffrey K. Harrison", "Françoise Brignole-Baudouin", "Serge Picaud", "Françoise Baleux", "José A. Sahel", "William Rostène", "Christophe Baudouin"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0037873.s001", "https://dx.doi.org/10.1371/journal.pone.0037873.s002", "https://dx.doi.org/10.1371/journal.pone.0037873.s003"], "stats"=>{"downloads"=>13, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CXCR3_Antagonism_of_SDF_1_5_67_Restores_Trabecular_Function_and_Prevents_Retinal_Neurodegeneration_in_a_Rat_Model_of_Ocular_Hypertension/124282", "title"=>"CXCR3 Antagonism of SDF-1(5-67) Restores Trabecular Function and Prevents Retinal Neurodegeneration in a Rat Model of Ocular Hypertension", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-06-04 01:11:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/628218"], "description"=>"<p><i>(A,B)</i> SDF-1(5-67), a truncated form of CXCL12, is detected in the human glaucomatous trabecular cell line HTM3 using a specific anti-SDF-1(5-67) neoepitope antibody. MMP inhibitors batimastat (100 nM) and TIMP-1 (0.5 nM) induce a decrease in SDF-1(5-67) production, whereas TNF-α (50 ng/mL [2.9 nM]) and TGF-β2 (10 ng/mL [0.8 nM]) enhance the production of SDF-1(5-67). ** <i>P</i><0.01. Exogenous SDF-1(5-67) and CXCL12 were used as positive and negative controls respectively for the antibody specificity as presented in the upper membrane (controls) of a representative western blot <i>(A)</i> taken from three independent experiments. Data in bar graphs are presented as means ± SEM.</p>", "links"=>[], "tags"=>["glaucomatous", "trabecular", "cells"], "article_id"=>298694, "categories"=>["Physiology", "Neuroscience", "Cell Biology", "Medicine"], "users"=>["Alexandre Denoyer", "David Godefroy", "Isabelle Célérier", "Julie Frugier", "Julie Degardin", "Jeffrey K. Harrison", "Françoise Brignole-Baudouin", "Serge Picaud", "Françoise Baleux", "José A. Sahel", "William Rostène", "Christophe Baudouin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037873.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Human_glaucomatous_trabecular_cells_produce_SDF_1_5_67_/298694", "title"=>"Human glaucomatous trabecular cells produce SDF-1(5-67).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-04 02:24:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/628643"], "description"=>"<p><i>(A,B)</i> Ocular hypertension during 3 months is associated with a degradation in the visual function <i>(A)</i> as assessed by the duration of visual tracking during a 1-min optokinetic testing (spatial frequency, 0.5 cycle/degree), and with a decrease in retinal nerve fiber density <i>(B)</i> as measured <i>in vivo</i> by scanning light ophthalmoscopy. Ophthalmic treatment with CXCR3 antagonist significantly protects the visual function and prevents retinal nerve fiber loss (n = 10 each). <i>(C)</i> Ocular hypertension during one month is associated with an increase in retinal ganglion cell apoptosis (reported as the number of TUNEL-labeled cells normalized to the observed retinal layer length), which is reversed 15 days after the treatment with CXCR3 antagonist (n = 10 each). ** <i>P</i><0.01 vs. normotensive eyes, §§ <i>P</i><0.01 vs. untreated hypertensive eyes. Data in graphs are presented as means ± SEM.</p>", "links"=>[], "tags"=>["antagonism-induced", "lowering", "intraocular", "prevents", "retinal", "neurodegeneration", "protects", "ocular"], "article_id"=>299118, "categories"=>["Physiology", "Neuroscience", "Cell Biology", "Medicine"], "users"=>["Alexandre Denoyer", "David Godefroy", "Isabelle Célérier", "Julie Frugier", "Julie Degardin", "Jeffrey K. Harrison", "Françoise Brignole-Baudouin", "Serge Picaud", "Françoise Baleux", "José A. Sahel", "William Rostène", "Christophe Baudouin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037873.g006", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CXCR3_antagonism_induced_lowering_of_intraocular_pressure_prevents_retinal_neurodegeneration_and_protects_visual_function_in_a_rat_model_of_ocular_hypertension_/299118", "title"=>"CXCR3 antagonism-induced lowering of intraocular pressure prevents retinal neurodegeneration and protects visual function in a rat model of ocular hypertension.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-04 02:31:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/628093"], "description"=>"<p><i>(A–C)</i> The chemokine CXCL12 <i>(A)</i> and receptors CXCR3 <i>(B)</i> and CXCR4 <i>(C)</i> are detected in unstimulated human glaucomatous trabecular cells HTM3 by indirect immunofluorescence (secondary antibody in green, propidium iodide in red, scale bar: 50 µm, magnification ×200). <i>(D)</i> Chemokine receptor CXCR4 appears as distinct spots located at the cell membrane surface (scale bar: 5 µm, mag. ×800). Representative images of three independent experiments are depicted. <i>(D)</i> Cell expression of CXCL12 and receptors is also detected and quantified by immunoflowcytometry. Representative results obtained over 6 independent experiments, mean ± SEM of positive cells. <i>(E)</i> Chemokine and receptor mRNAs are detected in human glaucomatous trabecular tissues (n = 15) and in the HTM3 trabecular cell line. Data in the bar graph are presented as means ± SEM.</p>", "links"=>[], "tags"=>["cxcr4", "glaucomatous", "trabecular"], "article_id"=>298571, "categories"=>["Physiology", "Neuroscience", "Cell Biology", "Medicine"], "users"=>["Alexandre Denoyer", "David Godefroy", "Isabelle Célérier", "Julie Frugier", "Julie Degardin", "Jeffrey K. Harrison", "Françoise Brignole-Baudouin", "Serge Picaud", "Françoise Baleux", "José A. Sahel", "William Rostène", "Christophe Baudouin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037873.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CXCL12_CXCR3_and_CXCR4_expression_by_human_glaucomatous_trabecular_tissue_and_a_trabecular_cell_line_/298571", "title"=>"CXCL12, CXCR3, and CXCR4 expression by human glaucomatous trabecular tissue and a trabecular cell line.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-04 02:22:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/628449"], "description"=>"<p><i>(A)</i> A single administration of CXCR3 antagonist (NBI-74330, 1 µM, 100 µL) induces a transient decrease in intraocular pressure (n = 10 in each group). <i>(B)</i> When the antagonist is administrated twice, intraocular pressure remains low during 6 weeks (n = 10 each); the black arrow indicates the period of retinal and visual <i>in vivo</i> testing presented in <i>Fig. 6A,B</i>. <i>(C)</i> Dose-dependent effect of two administrations of CXCR3 antagonist on intraocular pressure as tested two weeks after the treatment (n = 5 each). * <i>P</i><0.05, ** <i>P</i><0.01. Data in graphs are presented as means ± SEM.</p>", "links"=>[], "tags"=>["cxcr3", "antagonist", "decreases", "intraocular", "ocular"], "article_id"=>298917, "categories"=>["Physiology", "Neuroscience", "Cell Biology", "Medicine"], "users"=>["Alexandre Denoyer", "David Godefroy", "Isabelle Célérier", "Julie Frugier", "Julie Degardin", "Jeffrey K. Harrison", "Françoise Brignole-Baudouin", "Serge Picaud", "Françoise Baleux", "José A. Sahel", "William Rostène", "Christophe Baudouin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037873.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ophthalmic_administration_of_CXCR3_antagonist_decreases_intraocular_pressure_in_a_rat_model_of_ocular_hypertension_/298917", "title"=>"Ophthalmic administration of CXCR3 antagonist decreases intraocular pressure in a rat model of ocular hypertension.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-04 02:28:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/628305"], "description"=>"<p><i>(A)</i> 24-h incubation with CXCL12 (10 ng/mL [1.3 nM]) protects HTM3 cells from apoptotic stress induced by 15-min exposure to 0.01% benzalkonium chloride (BAC), whereas SDF-1(5-67) (10 ng/mL [1.3 nM]) increases apoptosis as assessed by microplate cytometry using Hoechst dye. ** <i>P</i><0.05 vs. unstressed cells, § <i>P</i><0.05 and §§ <i>P</i><0.01 vs. BAC-exposed cells. <i>(B)</i> The protective effect of CXCL12 (10 ng/mL, 24 h) is reversed by CXCR4 antagonist (AMD-3100, 1 µM), whereas the apoptotic effect of SDF-1(5-67) (10 ng/mL, 24 h) is inhibited by CXCR3 antagonist (NBI-74330, 1 µM). CXCL10 (10 ng/mL [1.1 nM], 24 h), a conventional ligand for CXCR3, mimics the apoptotic effect of SDF-1(5-67). ** <i>P</i><0.01. <i>(C)</i> Dose-dependent effect of 24-h incubation with SDF-1(5-67) or with CXCL12. ** <i>P</i><0.01 vs. CXCL12. <i>(D)</i> SDF-1(5-67) (10 ng/mL) increases caspase-3 activation as assessed by immunoflowcytometry. CXCR3 antagonist (NBI-74330, 1 µM) inhibits SDF-1(5-67)-induced caspase 3 activation. ** <i>P</i><0.01 vs. unstimulated, §§ <i>P</i><0.01 vs. SDF-1(5-67)-stimulated. Data in graphs are presented as means ± SEM.</p>", "links"=>[], "tags"=>["protects", "trabecular", "cells", "apoptosis", "induces", "cxcr3", "caspase-3"], "article_id"=>298771, "categories"=>["Physiology", "Neuroscience", "Cell Biology", "Medicine"], "users"=>["Alexandre Denoyer", "David Godefroy", "Isabelle Célérier", "Julie Frugier", "Julie Degardin", "Jeffrey K. Harrison", "Françoise Brignole-Baudouin", "Serge Picaud", "Françoise Baleux", "José A. Sahel", "William Rostène", "Christophe Baudouin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037873.g003", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CXCL12_protects_trabecular_cells_from_apoptosis_via_CXCR4_whereas_SDF_1_5_67_induces_apoptosis_through_CXCR3_and_caspase_3_activation_/298771", "title"=>"CXCL12 protects trabecular cells from apoptosis <i>via</i> CXCR4, whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase-3 activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-04 02:26:11"}

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Relative Metric

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