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Originally published In Press as doi:10.1167/iovs.08-2756 on December 20, 2008
 (Investigative Ophthalmology and Visual Science. 2009;50:1739-1745.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-2756
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Nucleotide Oligomerization Domain-2 (NOD2)-Induced Uveitis: Dependence on IFN-{gamma}

Holly L. Rosenzweig,1 Tatsushi Kawaguchi,1 Tammy M. Martin,1 Stephen R. Planck,1 Michael P. Davey,2 and James T. Rosenbaum1

1From the Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; and the 2Veterans Affairs Medical Center, Portland, Oregon.

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-{gamma}, in order to gain insight into downstream functional consequences of NOD2 activation within the eye triggering uveitis.

METHODS. Mice deficient in IFN-{gamma}, NOD2, or CD11b and their wild-type controls were treated with intravitreal injection of MDP in the presence or absence of IFN-{gamma}. IFN-{gamma} production 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-{gamma} within the eye. Deficiency in IFN-{gamma} diminished the development of MDP-induced uveitis, indicating its crucial role in downstream inflammatory events triggered by NOD2. Moreover, exogenous IFN-{gamma} markedly exacerbated MDP-induced ocular inflammation in a NOD2-dependent mechanism. The potential of IFN-{gamma} to enhance inflammation required the adhesion molecule CD11b because CD11b-deficient mice failed to show the synergistic effects of IFN-{gamma} and MDP cotreatment on adhering and infiltrating cells.

CONCLUSIONS. IFN-{gamma} was identified as a downstream mediator of NOD2-driven inflammation and the capacity of IFN-{gamma} in vivo to enhance the inflammatory potential of NOD2 was demonstrated. Extrapolation of these findings in mice suggests that the dysregulation of IFN-{gamma} may occur in patients with Blau syndrome, thereby contributing to the granulomatous nature of the disease.






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