Leukocyte Diapedesis In Vivo Induces Transient Loss of Tight Junction Protein at the Blood–Retina Barrier

Abstract

PURPOSE.Although much is now understood about the molecular structure of tight junctions (TJs), little is known about the regulation of their function during neural inflammatory disease processes in vivo. The mechanisms by which leukocytes transmigrate the blood-retina barrier (BRB) without affecting endothelial permeability are controversial. METHODS. Confocal immunofluorescence microscopy of ex vivo retinal wholemounts was used to study BRB integrity during leukocyte adhesion and migration during experimental autoimmune uveoretinitis (EAU). Western blot analysis was used to measure levels of TJ proteins in EAU retina and RPE and in normal retina or RPE cultured with cytokines or chemokines. RESULTS. No evidence for discontinuity or other weakness of the endothelial or epithelial barrier at tricellular corners was observed, and maximum disruption of TJ protein expression was focused in retinal venules correlating with sites of leukocyte extravasation. Areas of maximum TJ protein loss in vivo also correlated with redistribution or loss of ensheathing astrocyte processes on venules but not adjacent capillaries or arterioles. Exposure of normal choroidal and retinal explants ex vivo to cytokines and chemokines alone did not downregulate total occludin-1 or claudin-3 TJ protein expression. CONCLUSIONS. The data presented herein support an active role for leukocytes in TJ disruption and blood-retina barrier (BRB) breakdown during retinal inflammation and further implicate venule microenvironment as a key factor in leukocyte recruitment to retinal tissue in vivo. (Invest Ophthalmol Vis Sci. 2005;

Vitreous levels of interleukine-8 and monocyte chemoattractant protein-1 in macular oedema with branch retinal vein occlusion

“…10 MCP-1 significantly reduced ZO-1 protein expression in a mouse model of experimental autoimmune uveoretinitis. 24 Recently, Funk et al 25 reported elevated aqueous humour levels of IL-8 and MCP-1 in patients with CRVO, but not in those with BRVO. In this study we investigated whether IL-8 or MCP-1 are related with macular oedema in patients with BRVO by measuring the vitreous fluid levels of these chemokines.…”

Bacterial endophthalmitis: Therapeutic challenges and host–pathogen interactions

“…Inflammatory mediator production in this area likely exacerbates and maintains the inflammatory response, which can result in loss of vision (Koizumi, et al, 2003). During experimental autoimmune uveitis, leukocytes have been shown to have an active role in tight junction disruption and blood retinal barrier breakdown during retinal inflammation (Xu, et al, 2005).…”

Rho/Rho-associated Kinase-II Signaling Mediates Disassembly of Epithelial Apical Junctions

“…The AJC is a highly dynamic structure and may be rapidly and reversibly disassembled in different physiological and pathological circumstances, such as spermatogenesis (Lui and Lee, 2006), epithelial-mesenchymal transition (Grunert et al, 2003), during bacterial and viral invasion (Hecht et al, 1988;Spitz et al, 1995), and diapedesis (Sandig et al, 1997;Xu et al, 2005). Nevertheless, the signaling pathways regulating AJC disassembly remain enigmatic.…”

“…Several AJ and TJ cytosolic plaque proteins have been shown to directly interact with F-actin (Mege et al, 2006) and myosin (Cordenonsi et al, 1999). Such interactions are likely to mediate the attachment of the AJC to the perijunctional actomyosin bundles, and they are thought to stabilize apical junctions and regulate their dynamics (Turner, 2000).The AJC is a highly dynamic structure and may be rapidly and reversibly disassembled in different physiological and pathological circumstances, such as spermatogenesis (Lui and Lee, 2006), epithelial-mesenchymal transition (Grunert et al, 2003), during bacterial and viral invasion (Hecht et al, 1988;Spitz et al, 1995), and diapedesis (Sandig et al, 1997;Xu et al, 2005). Nevertheless, the signaling pathways regulating AJC disassembly remain enigmatic.…”