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T. Kawaguchi, S. R. Planck, T. M. Martin, H. Sawkar, M. P. Davey, J. T. Rosenbaum, H. L. Rosenzweig; Activation of Nod2, the Gene Responsible for Blau Syndrome, Induces Murine Eye Inflammation That Is Dependent on Interferon-Gamma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5140.
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NOD2 (nucleotide oligomerization binding domain 2) is involved in innate immunity to sense the component of bacterial peptidoglycan: muramyl dipeptide (MDP). Specific mutations in the human NOD2 gene cause an autosomal dominant form of granulomatous uveitis, arthritis and dermatitis called Blau Syndrome. To investigate how NOD2 triggers uveitis, we recently established a mouse model of MDP-induced ocular inflammation and demonstrated that the resulting intravascular inflammation in the iris is dependent on NOD2. Here we sought to investigate the role of the inflammatory cytokine interferon gamma (IFNγ) in MDP-induced uveitis in vivo in mice.
One hundred micrograms of MDP or saline was injected into the vitreous of BALB/c mice or mice deficient in IFNγ or in NOD2. The intravascular inflammatory response within the iris was assessed by intravital microscopy at 6 hours following MDP treatment and the numbers of rolling and adherent cells were quantified. Production of IFNγ was measured in eye homogenates by ELISA at different times following treatment with MDP or saline.
We found that MDP treatment resulted in a significant increase in IFNγ production within the eyes of BALB/c mice at 3 hours and 6 hours following treatment. IFNγ was no longer upregulated at 24 hours. Importantly, the increase in IFNγ in response to MDP was absent in NOD2 knock-out mice, which indicates an essential role for NOD2 in IFNγ production. We also demonstrated that IFNγ contributes to the intravascular inflammatory response to MDP, as IFNγ knock-out mice showed a significant decrease in the numbers of rolling and adhering cells within the iris vasculature in response to MDP.
In marked contrast to IL-1β, which we report elsewhere is not a mediator of MDP-induced uveitis, IFNγ plays an important role in promoting MDP-induced ocular inflammation. Extrapolating from these studies in mice suggests that IFNγ inhibition could be therapeutically beneficial in Blau syndrome.
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