Nucleotide oligomerization domain-2 (NOD2)-induced uveitis: dependence on IFN-gamma

• Published in: Investigative ophthalmology & visual science 2009-04, Vol.50 (4), p.1739-1745
• Main Authors: Rosenzweig, Holly L, Kawaguchi, Tatsushi, Martin, Tammy M, Planck, Stephen R, Davey, Michael P, Rosenbaum, James T
• Format: Article
• Language: English
• Subjects: Acetylmuramyl-Alanyl-Isoglutamine - toxicity; Adjuvants, Immunologic; Animals; CD11b Antigen - metabolism; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Interferon-gamma - metabolism; Iris Diseases - immunology; Iris Diseases - pathology; Leukocytes - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nod2 Signaling Adaptor Protein - physiology; Uveitis - chemically induced; Uveitis - immunology; Uveitis - pathology
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.08-2756

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. 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. 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. 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.