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

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33 Scopus citations

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 1 2009

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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