CXCR4 but not CXCR7 is mainly implicated in ocular leukocyte trafficking during ovalbumin-induced acute uveitis

Zili Zhang, Wenwei Zhong, Mark J. Hall, Peter Kurre, Doran Spencer, Amy Skinner, Stacy O'Neill, Zhenwei Xia, James (Jim) Rosenbaum

Research output: Contribution to journalArticle

17 Citations (Scopus)

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-1α) 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.

Original languageEnglish (US)
Pages (from-to)522-531
Number of pages10
JournalExperimental Eye Research
Volume89
Issue number4
DOIs
StatePublished - Oct 2009

Fingerprint

Uveitis
Ovalbumin
Leukocytes
T-Lymphocytes
Chemokine Receptors
Neutrophils
Eye Diseases
Neutralizing Antibodies
Intraperitoneal Injections
Real-Time Polymerase Chain Reaction
Monocytes
Anti-Inflammatory Agents
Up-Regulation
Endothelial Cells
Animal Models
Immunohistochemistry
Cytokines
Ligands
Inflammation
Antigens

Keywords

  • CXCL12
  • CXCR4
  • CXCR7
  • monocytes
  • neutrophils
  • ocular inflammation
  • T cells
  • uveitis

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

CXCR4 but not CXCR7 is mainly implicated in ocular leukocyte trafficking during ovalbumin-induced acute uveitis. / Zhang, Zili; Zhong, Wenwei; Hall, Mark J.; Kurre, Peter; Spencer, Doran; Skinner, Amy; O'Neill, Stacy; Xia, Zhenwei; Rosenbaum, James (Jim).

In: Experimental Eye Research, Vol. 89, No. 4, 10.2009, p. 522-531.

Research output: Contribution to journalArticle

Zhang, Zili ; Zhong, Wenwei ; Hall, Mark J. ; Kurre, Peter ; Spencer, Doran ; Skinner, Amy ; O'Neill, Stacy ; Xia, Zhenwei ; Rosenbaum, James (Jim). / CXCR4 but not CXCR7 is mainly implicated in ocular leukocyte trafficking during ovalbumin-induced acute uveitis. In: Experimental Eye Research. 2009 ; Vol. 89, No. 4. pp. 522-531.
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T1 - CXCR4 but not CXCR7 is mainly implicated in ocular leukocyte trafficking during ovalbumin-induced acute uveitis

AU - Zhang, Zili

AU - Zhong, Wenwei

AU - Hall, Mark J.

AU - Kurre, Peter

AU - Spencer, Doran

AU - Skinner, Amy

AU - O'Neill, Stacy

AU - Xia, Zhenwei

AU - Rosenbaum, James (Jim)

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N2 - 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-1α) 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.

AB - 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-1α) 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.

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