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Rôle des chimiokines CXCL12 et CXCL1 dans la physiopathologie du trabéculum et de la surface oculaire au cours du glaucome

Abstract : Glaucoma is the first cause of irreversible blindness in the world. Primary open-angle glaucoma (POAG) mostly combines retinal neuropathy with abnormal elevation of the intraocualar pressure, which is the first risk factor for the disease. Ocular hypertension is caused by a trabecular meshwork degeneration whose primary mecanisms are still unknown. Indeed, the current antiglaucoma treatment does not target the intial trabecular pathology so it is not currative. Moreover, antiglaucoma eye drops often contain a preservative, such as benzalkonium chloride (BAC), which has been demonstrated to cause ocular surface inflammation in glaucomatous patients treated over a long term period. Chemokines, small proteins from the cytokine family, have been first described for their chemotactic properties for leukocytes through their interaction with G protein coupled receptors. Aside from its immune properties, the chemokine CXCL12 is involved in the regulation of cell viability and extracellulare matrix remodelling through its receptor CXCR4. Recently, it has been reported that proteolytic cleavage of CXCL12 yields a proapoptotic form, SDF-1(5-67), acting via another chemokine receptor :CXCR3. In this thesis, CXCL12, CXCR3 and CXCR4 have been detected in trabecular cells in human glaucomatous trabecular tissue and immortalized cell line. We originally describe a balance between the protective system CXCL12/CXCR4 and SDF-1(5-67)/CXCR3 which induces trabecular apoptosis under the control of cytokines and matrix metalloproteinases known to be involved in POAG. We report the sucessful use in vivo of a non-peptide specific antagonist of CXCR3 in reducing ocular hypertension and restoring trabecular function in an animal model of glaucoma, opening up new therapeutic avenues in glaucoma. We also studied the role of another chamokine, CX3CL1, in the ocular surface inflammation induced by BAC. CX3CL1 is charaterized by powerful chemoattract properties on CX3CR1-bearing leukocytes. In this study, we report an overexpression of CX3CL1 in conjunctival epithelial cells in glaucomatous patients treated with a BAC-containing medication. In vitro, we demonstrate that BAC-stimulated conjunctival epithelial cells attract lymphocytic and monocytic subpopulations by producing CX3CL1. In an animal model of BAC-induced ocular toxicity, we report a decrease in macrophage infiltration to the conjunctiva in CX3CR1-deficient mice compared to wild-type animals, further confirming that CX3CL1/CX3CR1 is involved in immune cell trafincking in the ocular surface. Our results originally show that chemokines are involved in the pathophysiology of the anterior segment in glaucoma. Chemokines appear as a new regulating system for the pathogenesis of trabecular degeneration in glaucoma as well as for ocular surface inflammation, and could constitute new specific therapeutic targets in such deleterious diseases
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Submitted on : Wednesday, May 22, 2013 - 12:43:46 PM
Last modification on : Wednesday, December 9, 2020 - 3:16:53 PM
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  • HAL Id : tel-00824694, version 1

Citation

Alexandre Denoyer. Rôle des chimiokines CXCL12 et CXCL1 dans la physiopathologie du trabéculum et de la surface oculaire au cours du glaucome. Physiologie [q-bio.TO]. Université Pierre et Marie Curie - Paris VI, 2011. Français. ⟨NNT : 2011PA066079⟩. ⟨tel-00824694⟩

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