Nucleotide oligomerization domain-2 (NOD2)-induced uveitis: Dependence on IFN-γ

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Abstract

Purpose: Nucleotide oligomerization domain-2 (NOD2) plays an important role in innate immunity to sense muramyl dipeptide (MDP), a component of bacterial cell walls. Notably, NOD2 is linked to eye inflammation because mutations in NOD2 cause a granulomatous type of uveitis called Blau syndrome. A mouse model of NOD2-dependent ocular inflammation was employed to test the role of a cytokine strongly implicated in granuloma formation, IFN-γ, in order to gain insight into downstream functional consequences of NOD2 activation within the eye triggering uveitis. Methods: Mice deficient in IFN-γ, NOD2, or CD11b and their wild-type controls were treated with intravitreal injection of MDP in the presence or absence of IFN-γ. IFN-γproduction in the eye was measured by ELISA. The intravascular inflammatory response within the iris was quantified by intravital microscopy. Results: NOD2 activation resulted in the production of IFN-γwithin the eye. Deficiency in IFN-γdiminished the development of MDP-induced uveitis, indicating its crucial role in downstream inflammatory events triggered by NOD2. Moreover, exogenous IFN-γmarkedly exacerbated MDP-induced ocular inflammation in a NOD2-dependent mechanism. The potential of IFN-γto enhance inflammation required the adhesion molecule CD11b because CD11b-deficient mice failed to show the synergistic effects of IFN-γand MDP cotreatment on adhering and infiltrating cells. Conclusions: IFN-γwas identified as a downstream mediator of NOD2-driven inflammation and the capacity of IFN-γin vivo to enhance the inflammatory potential of NOD2 was demonstrated. Extrapolation of these findings in mice suggests that the dysregulation of IFN-γmay occur in patients with Blau syndrome, thereby contributing to the granulomatous nature of the disease.

Original languageEnglish (US)
Pages (from-to)1739-1745
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume50
Issue number4
DOIs
StatePublished - Apr 2009

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Uveitis
Nucleotides
Acetylmuramyl-Alanyl-Isoglutamine
Inflammation
Intravitreal Injections
Iris
Granuloma
Innate Immunity
Cell Wall
Enzyme-Linked Immunosorbent Assay
Cytokines
Mutation

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

@article{02e424315b7940c8860a4ebb738909d4,
title = "Nucleotide oligomerization domain-2 (NOD2)-induced uveitis: Dependence on IFN-γ",
abstract = "Purpose: Nucleotide oligomerization domain-2 (NOD2) plays an important role in innate immunity to sense muramyl dipeptide (MDP), a component of bacterial cell walls. Notably, NOD2 is linked to eye inflammation because mutations in NOD2 cause a granulomatous type of uveitis called Blau syndrome. A mouse model of NOD2-dependent ocular inflammation was employed to test the role of a cytokine strongly implicated in granuloma formation, IFN-γ, in order to gain insight into downstream functional consequences of NOD2 activation within the eye triggering uveitis. Methods: Mice deficient in IFN-γ, NOD2, or CD11b and their wild-type controls were treated with intravitreal injection of MDP in the presence or absence of IFN-γ. IFN-γproduction in the eye was measured by ELISA. The intravascular inflammatory response within the iris was quantified by intravital microscopy. Results: NOD2 activation resulted in the production of IFN-γwithin the eye. Deficiency in IFN-γdiminished the development of MDP-induced uveitis, indicating its crucial role in downstream inflammatory events triggered by NOD2. Moreover, exogenous IFN-γmarkedly exacerbated MDP-induced ocular inflammation in a NOD2-dependent mechanism. The potential of IFN-γto enhance inflammation required the adhesion molecule CD11b because CD11b-deficient mice failed to show the synergistic effects of IFN-γand MDP cotreatment on adhering and infiltrating cells. Conclusions: IFN-γwas identified as a downstream mediator of NOD2-driven inflammation and the capacity of IFN-γin vivo to enhance the inflammatory potential of NOD2 was demonstrated. Extrapolation of these findings in mice suggests that the dysregulation of IFN-γmay occur in patients with Blau syndrome, thereby contributing to the granulomatous nature of the disease.",
author = "Holly Rosenzweig and Tatsushi Kawaguchi and Tammy Martin and Stephen Planck and Michael Davey and Rosenbaum, {James (Jim)}",
year = "2009",
month = "4",
doi = "10.1167/iovs.08-2756",
language = "English (US)",
volume = "50",
pages = "1739--1745",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "4",

}

TY - JOUR

T1 - Nucleotide oligomerization domain-2 (NOD2)-induced uveitis

T2 - Dependence on IFN-γ

AU - Rosenzweig, Holly

AU - Kawaguchi, Tatsushi

AU - Martin, Tammy

AU - Planck, Stephen

AU - Davey, Michael

AU - Rosenbaum, James (Jim)

PY - 2009/4

Y1 - 2009/4

N2 - Purpose: Nucleotide oligomerization domain-2 (NOD2) plays an important role in innate immunity to sense muramyl dipeptide (MDP), a component of bacterial cell walls. Notably, NOD2 is linked to eye inflammation because mutations in NOD2 cause a granulomatous type of uveitis called Blau syndrome. A mouse model of NOD2-dependent ocular inflammation was employed to test the role of a cytokine strongly implicated in granuloma formation, IFN-γ, in order to gain insight into downstream functional consequences of NOD2 activation within the eye triggering uveitis. Methods: Mice deficient in IFN-γ, NOD2, or CD11b and their wild-type controls were treated with intravitreal injection of MDP in the presence or absence of IFN-γ. IFN-γproduction in the eye was measured by ELISA. The intravascular inflammatory response within the iris was quantified by intravital microscopy. Results: NOD2 activation resulted in the production of IFN-γwithin the eye. Deficiency in IFN-γdiminished the development of MDP-induced uveitis, indicating its crucial role in downstream inflammatory events triggered by NOD2. Moreover, exogenous IFN-γmarkedly exacerbated MDP-induced ocular inflammation in a NOD2-dependent mechanism. The potential of IFN-γto enhance inflammation required the adhesion molecule CD11b because CD11b-deficient mice failed to show the synergistic effects of IFN-γand MDP cotreatment on adhering and infiltrating cells. Conclusions: IFN-γwas identified as a downstream mediator of NOD2-driven inflammation and the capacity of IFN-γin vivo to enhance the inflammatory potential of NOD2 was demonstrated. Extrapolation of these findings in mice suggests that the dysregulation of IFN-γmay occur in patients with Blau syndrome, thereby contributing to the granulomatous nature of the disease.

AB - Purpose: Nucleotide oligomerization domain-2 (NOD2) plays an important role in innate immunity to sense muramyl dipeptide (MDP), a component of bacterial cell walls. Notably, NOD2 is linked to eye inflammation because mutations in NOD2 cause a granulomatous type of uveitis called Blau syndrome. A mouse model of NOD2-dependent ocular inflammation was employed to test the role of a cytokine strongly implicated in granuloma formation, IFN-γ, in order to gain insight into downstream functional consequences of NOD2 activation within the eye triggering uveitis. Methods: Mice deficient in IFN-γ, NOD2, or CD11b and their wild-type controls were treated with intravitreal injection of MDP in the presence or absence of IFN-γ. IFN-γproduction in the eye was measured by ELISA. The intravascular inflammatory response within the iris was quantified by intravital microscopy. Results: NOD2 activation resulted in the production of IFN-γwithin the eye. Deficiency in IFN-γdiminished the development of MDP-induced uveitis, indicating its crucial role in downstream inflammatory events triggered by NOD2. Moreover, exogenous IFN-γmarkedly exacerbated MDP-induced ocular inflammation in a NOD2-dependent mechanism. The potential of IFN-γto enhance inflammation required the adhesion molecule CD11b because CD11b-deficient mice failed to show the synergistic effects of IFN-γand MDP cotreatment on adhering and infiltrating cells. Conclusions: IFN-γwas identified as a downstream mediator of NOD2-driven inflammation and the capacity of IFN-γin vivo to enhance the inflammatory potential of NOD2 was demonstrated. Extrapolation of these findings in mice suggests that the dysregulation of IFN-γmay occur in patients with Blau syndrome, thereby contributing to the granulomatous nature of the disease.

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