1. 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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William Rostène, Julie Frugier, Françoise Baleux, David Godefroy, Isabelle Célérier, Serge Picaud, Françoise Brignole-Baudouin, Julie Degardin, Jeffrey K. Harrison, Christophe Baudouin, José Sahel, Alexandre Denoyer, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche des Cordeliers - Equipe 20 'ingénierie des connaissances en santé', Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Florida [Gainesville] (UF), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Chimie des biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), CIC Quinze-Vingts, Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Laboratory of Toxicology, Faculty of Pharmaceutical and Biological Sciences, Université Paris Descartes - Paris 5 ( UPD5 ), Chimie des Biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), This work was supported by INSERM grants for AD, DG, JD, WR and CB, by a UPMC grant for IC and JF, and by an NIH grant for JKH (AI058256)., Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) ( APHP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Godefroy, David
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Retinal degeneration ,Male ,Visual System ,Ocular hypertension ,Apoptosis ,MESH : Cytoprotection ,MESH : Receptors, CXCR4 ,MESH : Receptors, CXCR3 ,0302 clinical medicine ,MESH: Animals ,lcsh:Science ,MESH: Stress, Physiological ,MESH : Glaucoma ,0303 health sciences ,Neurodegeneration ,Anatomy ,MESH : Chemokine CXCL12 ,Sensory Systems ,3. Good health ,[SDV] Life Sciences [q-bio] ,MESH : Retinal Degeneration ,Medicine ,MESH: Chemokine CXCL12 ,MESH: Glaucoma ,medicine.medical_specialty ,MESH: Enzyme Activation ,Receptors, CXCR4 ,Receptors, CXCR3 ,MESH: Retinal Degeneration ,Ocular Anatomy ,Caspase 3 ,MESH: Receptors, CXCR4 ,MESH: Receptors, CXCR3 ,03 medical and health sciences ,Humans ,Rats, Long-Evans ,MESH: Vision, Ocular ,Biology ,Intraocular Pressure ,MESH: Humans ,[ SDV ] Life Sciences [q-bio] ,lcsh:R ,MESH : Humans ,Glaucoma ,medicine.disease ,MESH : Disease Models, Animal ,eye diseases ,Chemokine CXCL12 ,MESH: Cell Line ,MESH: Ocular Hypertension ,Enzyme Activation ,MESH: Cytoprotection ,Ophthalmology ,Endocrinology ,chemistry ,030221 ophthalmology & optometry ,Rat ,lcsh:Q ,Ocular Hypertension ,Trabecular meshwork ,MESH: Disease Models, Animal ,MESH : Apoptosis ,Neuroscience ,MESH : Cell Line ,Intraocular pressure ,Anatomy and Physiology ,genetic structures ,[SDV]Life Sciences [q-bio] ,MESH : Vision, Ocular ,lcsh:Medicine ,chemistry.chemical_compound ,MESH: Caspase 3 ,Molecular Cell Biology ,MESH : Caspase 3 ,MESH : Rats, Long-Evans ,MESH : Intraocular Pressure ,Multidisciplinary ,Cell Death ,MESH : Rats ,Retinal Degeneration ,Animal Models ,MESH : Trabecular Meshwork ,medicine.anatomical_structure ,Research Article ,MESH: Rats ,MESH : Male ,Cell Line ,Model Organisms ,MESH: Intraocular Pressure ,MESH: Rats, Long-Evans ,Stress, Physiological ,Trabecular Meshwork ,Ocular System ,Internal medicine ,medicine ,MESH : Ocular Hypertension ,Animals ,MESH : Stress, Physiological ,Vision, Ocular ,030304 developmental biology ,MESH: Apoptosis ,[ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Retinal ,MESH: Male ,Rats ,MESH: Trabecular Meshwork ,Disease Models, Animal ,Cytoprotection ,MESH : Animals ,sense organs ,MESH : Enzyme Activation - Abstract
International audience; 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.
- Published
- 2012
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