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H. L. Rosenzweig, T. Kawagushi, H. Sawkar, S. R. Planck, T. M. Martin, M. P. Davey, J. T. Rosenbaum; Identification of IFN as a Novel Regulator of NOD2-Mediated Uveitis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3032.
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NOD2 (nucleotide oligomerization binding domain 2) 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 as mutations in NOD2 cause a granulomatous uveitis called Blau Syndrome. Interferon gamma (IFNγ) is known to contribute to granuloma formation. We previously reported that IFNγ-deficient mice were protected against MDP-induced ocular inflammation. Here, we explored the mechanisms by which IFNγ might contribute to inflammation induced by NOD2 activation.
Mice deficient in NOD2 or CD11b and their wild-type controls were treated with an intravitreal injection of MDP in the presence or absence of IFNγ. The intravascular inflammatory response within the iris was quantified by intravital microscopy.
We found that IFNγ has the capacity to enhance NOD2 function in vivo as IFNγ co-treatment significantly exacerbated MDP-induced uveitis. Importantly, NOD2 deficiency abolished the synergistic effects of MDP and IFNγ indicating its essential role in this phenomenon. The potential of IFNγ to enhance inflammation required the adhesion molecule CD11b, as CD11b-deficient mice failed to show the synergistic effects from IFNγ and MDP co-treatment on adhering and infiltrating cells.
In NOD2-induced uveitis, IFNγ contributes to MDP-triggered uveitis and has the capacity to further regulate NOD2 function in vivo, thereby synergizing with MDP-induced ocular inflammation. Investigation of downstream signals induced by IFNγ could provide insight into pathological mechanisms of Blau syndrome.
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