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NOD2, the Gene Responsible for Familial Granulomatous Uveitis, in a Mouse Model of Uveitis

¹From the Casey Eye Institute and the ²Departments of Molecular Microbiology and Immunology, ⁴Medicine, and ⁵Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon; ³Veterans Affairs Medical Center, Portland, Oregon; and ⁶Department of Immunology, Yale University School of Medicine, New Haven, Connecticut.

PURPOSE. NOD2 plays an important role in the recognition of intracellular bacteria through its ability to sense the components of bacterial peptidoglycan (PGN), namely muramyl dipeptide (MDP) and muramyl tripeptide (MTP). Specific mutations in the human NOD2 gene cause Blau syndrome, an autosomal dominant form of uveitis, arthritis, and dermatitis. As a first step toward understanding the role of NOD2 in the pathogenesis of uveitis, the authors developed a mouse model of MDP-dependent uveitis.

METHODS. BALB/c mice and mice deficient in L-selectin or NOD2 received intravitreal injection of MDP, MTP, or PGN. The intravascular response within the iris and cellular infiltration was quantified by intravital microscopy and histologic assessment.

RESULTS. MDP induced an acute, ocular inflammatory response, wherein rolling and adhering leukocytes within the vasculature were significantly increased within 6 hours after MDP treatment. A minor increase in cellular infiltration occurred at 12 hours after MDP treatment. The adhesion molecule L-selectin participated in MDP-induced vascular inflammation because L-selectin knockout mice showed a significant decrease in the number of rolling cells. Importantly, NOD2 plays an essential role in ocular inflammation induced by MDP, as indicated by the fact that uveitis did not develop in Nod2 knockout mice in response to MDP. Nod2 knockout mice also showed abolished ocular inflammation in response to MTP but not to PGN treatment.

CONCLUSIONS. These findings demonstrate a novel mouse model of uveitis, wherein NOD2 plays an essential role in inflammation induced by the minimal components of PGN. Thus, innate immune responses mediated by NOD2 may participate in the development of uveitis in response to bacterial products.

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				H. L. Rosenzweig, T. M. Martin, S. R. Planck, K. Galster, M. M. Jann, M. P. Davey, K. Kobayashi, R. A. Flavell, and J. T. Rosenbaum Activation of NOD2 in vivo induces IL-1{beta} production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling J. Leukoc. Biol., August 1, 2008; 84(2): 529 - 536. [Abstract] [Full Text] [PDF]