title: CXCR4 but not CXCR7 is mainly implicated in ocular leukocyte trafficking during ovalbumin-induced acute uveitis.
abstract: Uveitis is an inflammatory ocular disease characterized by the infiltration of T lymphocytes and other leukocytes into 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-1alpha) 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. 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 transcriptional up-regulation of 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 (a specific CXCR4 antagonist) significantly attenuated OVA-induced uveitis and CXCL12-mediated transwell migration. In contrast, intraperitoneal administration of CXCR7 neutralizing antibody did not significantly alter ocular infiltration of inflammatory cells caused by OVA challenge. Our data suggest that CXCR4 but not CXCR7 plays a critical role in antigen-induced ocular inflammation by facilitating leukocyte infiltration. This study not only enhances our knowledge of the immunopathological mechanism of uveitis but also provides a novel rationale to target CXCR4 as an anti-inflammatory strategy to treat uveitis.
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.forename: Wenwei
authors.initials: W
authors.lastname: Zhong
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hall
authors.forename: Peter
authors.initials: P
authors.lastname: Kurre
authors.forename: Doran
authors.initials: D
authors.lastname: Spencer
authors.forename: Amy
authors.initials: A
authors.lastname: Skinner
authors.forename: Stacy
authors.initials: S
authors.lastname: O'Neill
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Xia
authors.forename: James T
authors.initials: JT
authors.lastname: Rosenbaum
mesh_terms: D000208:Acute Disease; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D001596:Benzylamines; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009504:Neutrophils / Q000502:physiology; D010047:Ovalbumin / Q000633:toxicity; D054387:Receptors, CXCR / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology
chemical_list: D057134:Antibodies, Neutralizing; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D010047:Ovalbumin; C088327:plerixafor