title: Bilateral neuroinflammatory processes in visual pathways induced by unilateral ocular hypertension in the rat.
abstract: BACKGROUND
  Glaucoma is one of the leading causes of irreversible blindness in the world. The major risk factor is elevated intraocular pressure (IOP) leading to progressive retinal ganglion cell (RGC) death from the optic nerve (ON) to visual pathways in the brain. Glaucoma has been reported to share mechanisms with neurodegenerative disorders. We therefore hypothesize that neuroinflammatory mechanisms in central visual pathways may contribute to the spread of glaucoma disease. The aim of the present study was to analyze the neuroinflammation processes that occur from the pathological retina to the superior colliculi (SCs) in a rat model of unilateral ocular hypertension induced by episcleral vein cauterization (EVC).
  
  
  RESULTS
  Six weeks after unilateral (right eye) EVC in male Long-Evans rats, we evaluated both the neurodegenerative process and the neuroinflammatory state in visual pathway tissues. RGCs immunolabeled (Brn3a(+)) in ipsilateral whole flat-mounted retina demonstrated peripheral RGC loss associated with tissue macrophage/microglia activation (CD68(+)). Gene expression analysis of hypertensive and normotensive retinas revealed a significant increase of pro-inflammatory genes such as CCL2, IL-1β, and Nox2 mRNA expression compared to naïve eyes. Importantly, we found an upregulation of pro-inflammatory markers such as IL-1β and TNFα and astrocyte and tissue macrophage/microglia activation in hypertensive and normotensive RGC projection sites in the SCs compared to a naïve SC. To understand how neuroinflammation in the hypertensive retina is sufficient to damage both right and left SCs and the normotensive retina, we used an inflammatory model consisting in an unilateral stereotaxic injection of TNFα (25 ng/μl) in the right SC of naïve rats. Two weeks after TNFα injection, using an optomotor test, we observed that rats had visual deficiency in both eyes. Furthermore, both SCs showed an upregulation of genes and proteins for astrocytes, microglia, and pro-inflammatory cytokines, notably IL-1β. In addition, both retinas exhibited a significant increase of inflammatory markers compared to a naïve retina.
  
  
  CONCLUSIONS
  All these data evidence the complex role played by the SCs in the propagation of neuroinflammatory events induced by unilateral ocular hypertension and provide a new insight into the spread of neurodegenerative diseases such as glaucoma.
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Sapienza
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Raveu
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Reboussin
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Roubeix
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Boucher
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dégardin
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Godefroy
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: William
authors.initials: W
authors.lastname: Rostène
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Reaux-Le Goazigo
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.|CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC, 28 rue de Charenton, 75012, Paris, France.|Department Ophthalmology, Hopital Ambroise Pare, AP HP, F-92100, Boulogne, France.|University Versailles St Quentin En Yvelines, F-78180, Montigny-Le-Bretonneux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Baudouin
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, Institut de la Vision, 17 rue Moreau, 75012, Paris, France. stephane.melik-parsadaniantz@inserm.fr.|INSERM U968, Institut de la Vision, 17 rue Moreau, 75012, Paris, France. stephane.melik-parsadaniantz@inserm.fr.|CNRS UMR_7210, Institut de la Vision, 17 rue Moreau, 75012, Paris, France. stephane.melik-parsadaniantz@inserm.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Melik Parsadaniantz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002772:Cholera Toxin / Q000493:pharmacokinetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications* / Q000473:pathology*; D007839:Functional Laterality / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009798:Ocular Hypertension / Q000209:etiology* / Q000473:pathology; D009907:Optometry; D009930:Organic Chemicals / Q000493:pharmacokinetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012165:Retinal Ganglion Cells / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D014795:Visual Pathways / Q000378:metabolism / Q000473:pathology*
chemical_list: C100745:Aif1 protein, rat; C417664:Alexa594; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009930:Organic Chemicals; D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha; D002772:Cholera Toxin