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Z. Zhang, W. Zhong, M. Hall, D. Spencer, P. Kurre, J. T. Rosenbaum; Blocking CXCR4 Attenuates Experimental Uveitis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2655.
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Uveitis is an inflammatory ocular disease characterized by the infiltration of T lymphocytes and other leukocytes in the eye. The recruitment of these inflammatory cells from systemic vasculature to ocular tissue is a well-coordinated multistep process including rolling, firm adhesion and transmigration. CXCL12 (SDF-1) is an endothelial cell-derived cytokine interacting with CXCR4 and CXCR7, two chemokine receptors mainly expressed in T cells, neutrophils and monocytes. Recent studies have shown that CXCR4, CXCR7 and their ligand, CXCL12, are important for the regulation of leukocyte mobilization and trafficking. However, it is unclear whether these two chemokine receptors are implicated in the pathogenesis of uveitis. In this study, we used DO11.10 mice, whose CD4+ T cells are genetically engineered to react with ovalbumin (OVA), to investigate the role of CXCR4 and CXCR7 in an animal model of uveitis.
Uveitis was induced by intravitreal injection of OVA in DO11.10 mice. At 24 hours after OVA injection, ocular inflammation was evaluated by intravital microscopy. Then, the mice were sacrificed and total RNA of the eyes was harvested to assess gene transcription. Moreover, splenocytes were isolated for in vitro transwell migration assay.
Intravital microscopy revealed that intravitreal OVA challenge of DO11.10 mice caused the infiltration of both T cells and neutrophils. The invasion of these inflammatory cells coincided with the detection of mRNA for CXCR4 and CXCR7 in the eye. In addition, both real time-PCR and immunohistochemistry revealed an enhanced expression of endothelial CXCL12. Furthermore, intraperitoneal injection of AMD3100 (100 µg) (a specific CXCR4 antagonist) significantly attenuated OVA-induced uveitis and CXCL12-induced in vitro transmigration. In contrast, intraperitoneal administration of CXCR7 (100 µg) neutralizing antibody did not alter ocular infiltration of inflammatory cells caused by OVA challenge.
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