Inhibition of vascular adhesion protein‐1 suppresses endotoxin‐induced uveitis

Noda, Kousuke; Miyahara, Shinya; Nakazawa, Toru; Almulki, L.; Nakao, Shintaro; Hisatomi, Toshio; She, Haicheng; Thomas, Kerry; Garland, Robert; Miller, Joan W.; Gragoudas, Evangelos S.; Kawai, Yosuke; Mashima, Yukihiko; Hafezi-Moghadam, Ali

doi:10.1096/fj.07-9377com

Cited by 50 publications

(56 citation statements)

References 37 publications

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“…Mice were evaluated at 3 h (for NF-kB activation), 6 h (for various gene expression) and 24 h (for leukocyte infiltration) after LPS injection, all of which are the established time points for evaluation of pathological parameters in EIU. [26][27][28] Cell Culture Primary human retinal microvascular endothelial cells (retinal microvasucular endothelial cells (HRMECs); Cell Systems, Kirkland, WA, USA), hTERT-RPE (retinal pigment epithelial cells), Y79 and RAW264.7 cells (American Type Culture Collection, Manassas, VA, USA) were purchased. All cell lines were cultured following the manufacturers' instructions.…”

Section: Methodsmentioning

confidence: 99%

“…[26][27][28] Briefly, the chest cavity was opened and a cannula was introduced into the left ventricle under deep anesthesia. After injection of PBS to remove erythrocytes and nonadherent leukocytes, FITCconjugated Con A was perfused.…”

Section: Quantification Of Retinal Adherent Leukocytesmentioning

confidence: 99%

“…27 Briefly, tissues were fixed and embedded in paraffin using standard techniques. Three 5-mm sections were prepared at a distance of 100 mm to each other with the middle section passing through the optic nerve.…”

Section: Quantification Of Vitreous Infiltrating Leukocytesmentioning

confidence: 99%

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Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

Kanda

Noda

Oike

et al. 2012

Laboratory Investigation

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Angiopoietin-like protein (Angptl) 2 is a key mediator linking obesity to chronic adipose-tissue inflammation and systemic insulin resistance, and increasing evidence has shown that Angptl2 is associated with various chronic inflammatory diseases such as cancer and dermatomyositis; however, it remains unclear that Angptl2 functions in acute inflammation. In this study, we investigate whether Angptl2 has a role in acute inflammation in the eye with endotoxin-induced uveitis (EIU). Angptl2 was widely expressed in the normal mouse retina, while Angptl2^[-/-] mice did not exhibit any changes in retinal cell marker expression and morphological analyses. Treatment with lipopolysaccharide (LPS) stimulated retinal Angptl2 mRNA expression in vivo and in vitro. We generated EIU in wild-type (C57BL/6) and Angptl2^[-/-] mice by injecting LPS intraperitoneally. Compared to wild-type animals, Angptl2^[-/-] mice significantly reduced various EIU-associated cellular and molecular parameters including leukocyte adhesion to the retinal vessels and infiltration into the vitreous cavity and retinal mRNA expression levels of monocyte chemotactic protein-1, intercellular adhesion molecule-1, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, together with nuclear translocation of nuclear factor (NF)-κB p65 subunit. In vitro, antibody-based inhibition of α5β1 integrin, a receptor for Angptl2, significantly repressed LPS-induced expression of IL-6 and TNF-α, both of which are the major inflammatory cytokines derived from macrophages. The present findings indicate that Angptl2 mediates endotoxin-induced retinal inflammation through the activation of NF-κB signaling pathway and suggest a potential validity of Angptl2 as a new molecular target for the treatment of acute inflammation

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Section: Methodsmentioning

confidence: 99%

Section: Quantification Of Retinal Adherent Leukocytesmentioning

confidence: 99%

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Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

Kanda

Noda

Oike

et al. 2012

Laboratory Investigation

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“…VAP-1 is expressed in pericytes and vascular endothelium and is involved in leukocyte extravasation to inflamed tissues. 1 Recently, we reported the expression of VAP-1 in the human eye 2 and the critical role it plays in ocular inflammatory diseases, such as uveitis, 3 age-related macular degeneration, 4 and diabetic retinopathy. 5 IL-1␤, a multipotent cytokine, is critically involved in the acute inflammatory response, activation and chemotaxis of inflammatory and antigen-presenting cells, up-regulation of adhesion molecules, and neovascularization.…”

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confidence: 99%

VAP-1–Mediated M2 Macrophage Infiltration Underlies IL-1β– but Not VEGF-A–Induced Lymph- and Angiogenesis

Nakao

Noda

Zandi

et al. 2011

The American Journal of Pathology

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Vascular adhesion protein-1 (VAP-1) contributes to inflammatory and angiogenic diseases, including cancer and age-related macular degeneration. It is expressed in blood vessels and contributes to inflammatory leukocyte recruitment. The cytokines IL-1␤ and vascular endothelial growth factor A (VEGF-A) modulate angiogenesis, lymphangiogenesis, and leukocyte infiltration. The lymphatic endothelium expresses intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which facilitate leukocyte transmigration into the lymphatic vessels. However, whether lymphatics express VAP-1 and whether they contribute to cytokine-dependent lymph-and angiogenesis are unknown. We investigated the role of VAP-1 in IL-1␤-and VEGF-A-induced lymph-and angiogenesis using the established corneal micropocket assay. IL-1␤ increased VAP-1 expression in the inflamed cornea. Our in vivo molecular imaging revealed significantly higher VAP-1 expression in neovasculature than in the preexisting vessels. VAP-1 was expressed in blood but not lymphatic vessels in vivo. IL-1␤-induced M2 macrophage infiltration and lymphand angiogenesis were blocked by VAP-1 inhibition. In contrast, VEGF-A-induced lymph-and angiogenesis were unaffected by VAP-1 inhibition. Our results indicate a key role for VAP-1 in lymph-and angiogenesisrelated macrophage recruitment. VAP-1 might become a new target for treatment of inflammatory lymph-and angiogenic diseases, including cancer.

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“…The anti-VAP-1 Abs inhibit leukocyte-endothelial interactions in several in vitro and in vivo models (8)(9)(10)(11)(12)(13)(14). The small-molecule SSAO inhibitors also effectively attenuate inflammation by diminishing leukocyte rolling, firm adhesion, and transmigration through multiple types of endothelial cells (9,13,(15)(16)(17)(18)(19)(20). Notably, the anti-VAP-1 Abs do not inhibit the enzymatic activity of VAP-1, and the enzyme inhibitors do not alter the mAb-defined surface epitopes of VAP-1 (8,15).…”

mentioning

confidence: 99%

Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice

Marttila-Ichihara

Castermans

Auvinen

et al. 2010

The Journal of Immunology

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Vascular adhesion protein-1 (VAP-1) is an endothelial, cell surface–expressed oxidase involved in leukocyte traffic. The adhesive function of VAP-1 can be blocked by anti–VAP-1 Abs and small-molecule inhibitors. However, the effects of VAP-1 blockade on antitumor immunity and tumor progression are unknown. In this paper, we used anti–VAP-1 mAbs and small-molecule inhibitors of VAP-1 in B16 melanoma and EL-4 lymphoma tumor models in C57BL/6 mice. Leukocyte accumulation into tumors and neoangiogenesis were evaluated by immunohistochemistry, flow cytometry, and intravital videomicroscopy. We found that both anti–VAP-1 Abs and VAP-1 inhibitors reduced the number of leukocytes in the tumors, but they targeted partially different leukocyte subpopulations. Anti–VAP-1 Abs selectively inhibited infiltration of CD8-positive lymphocytes into tumors and had no effect on accumulation of myeloid cells into tumors. In contrast, the VAP-1 inhibitors significantly reduced only the number of proangiogenic Gr-1+CD11b+ myeloid cells in melanomas and lymphomas. Blocking of VAP-1 by either means left tumor homing of regulatory T cells and type 2 immune-suppressing monocytes/macrophages intact. Notably, VAP-1 inhibitors, but not anti–VAP-1 Abs, retarded the growth of melanomas and lymphomas and reduced tumor neoangiogenesis. The VAP-1 inhibitors also reduced the binding of Gr-1+ myeloid cells to the tumor vasculature. We conclude that tumors use the catalytic activity of VAP-1 to recruit myeloid cells into tumors and to support tumor progression. Small-molecule VAP-1 inhibitors therefore might be a potential new tool for immunotherapy of tumors.

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Inhibition of vascular adhesion protein‐1 suppresses endotoxin‐induced uveitis

Cited by 50 publications

References 37 publications

Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

VAP-1–Mediated M2 Macrophage Infiltration Underlies IL-1β– but Not VEGF-A–Induced Lymph- and Angiogenesis

Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice

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