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.