TY - JOUR
T1 - Nucleotide oligomerization domain-2 (NOD2)-induced uveitis
T2 - Dependence on IFN-γ
AU - Rosenzweig, Holly L.
AU - Kawaguchi, Tatsushi
AU - Martin, Tammy M.
AU - Planck, Stephen R.
AU - Davey, Michael P.
AU - Rosenbaum, James T.
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
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U2 - 10.1167/iovs.08-2756
DO - 10.1167/iovs.08-2756
M3 - Article
C2 - 19098321
AN - SCOPUS:64049102506
SN - 0146-0404
VL - 50
SP - 1739
EP - 1745
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 4
ER -